Inhibitors of bruton&#39;s tyrosine kinase

ABSTRACT

This application discloses 5-phenyl-1H-pyridin-2-one and 6-phenyl-2H-pyridazin-3-one derivatives according to generic Formulae I-III: 
                         
wherein, variables R, X, Y 1 , Y 2 , Y 3 , Y 4 , n and m are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions containing compounds of Formulae I-III and at least one carrier, diluent or excipient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No 12/322,870,filed Feb. 5, 2009, now allowed which claims the benefit of U.S.provisional patent application Ser. No. 61/026,204 filed on Feb. 5,2008, U.S. provisional patent application Ser. No. 61/075,277 filed onJun. 24, 2008, and U.S. provisional patent application Ser. No.61/122,510, filed Dec. 15, 2008, the disclosures of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the use of novel derivatives whichinhibit Btk and are useful for the treatment of auto-immune andinflammatory diseases caused by aberrant B-cell activation. The novel5-phenyl-1H-pyridin-2-one and 6-phenyl-2H-pyridazin-3-one derivativesdescribed herein are useful for the treatment of arthritis.

BACKGROUND OF THE INVENTION

Protein kinases constitute one of the largest families of human enzymesand regulate many different signaling processes by adding phosphategroups to proteins (T. Hunter, Cell 1987 50:823-829). Specifically,tyrosine kinases phosphorylate proteins on the phenolic moiety oftyrosine residues. The tyrosine kinase family includes members thatcontrol cell growth, migration, and differentiation. Abnormal kinaseactivity has been implicated in a variety of human diseases includingcancers, autoimmune and inflammatory diseases. Since protein kinases areamong the key regulators of cell signaling they provide a target tomodulate cellular function with small molecular kinase inhibitors andthus make good drug design targets. In addition to treatment ofkinase-mediated disease processes, selective and efficacious inhibitorsof kinase activity are also useful for investigation of cell signalingprocesses and identification of other cellular targets of therapeuticinterest.

There is good evidence that B-cells play a key role in the pathogenesisof autoimmune and/or inflammatory disease. Protein-based therapeuticsthat deplete B cells such as Rituxan are effective againstautoantibody-driven inflammatory diseases such as rheumatoid arthritis(Rastetter et al. Annu Rev Med 2004 55:477). Therefore inhibitors of theprotein kinases that play a role in B-cell activation should be usefultherapeutics for B-cell mediated disease pathology such as autoantibodyproduction.

Signaling through the B-cell receptor (BCR) controls a range of B-cellresponses including proliferation and differentiation into matureantibody producing cells. The BCR is a key regulatory point for B-cellactivity and aberrant signaling can cause deregulated B-cellproliferation and formation of pathogenic autoantibodies that lead tomultiple autoimmune and/or inflammatory diseases. Bruton's TyrosineKinase (Btk) is a non-BCR associated kinase that is membrane proximaland immediately downstream from BCR. Lack of Btk has been shown to blockBCR signaling and therefore inhibition of Btk could be a usefultherapeutic approach to block B-cell mediated disease processes.

Btk is a member of the Tec family of tyrosine kinases, and has beenshown to be a critical regulator of early B-cell development and matureB-cell activation and survival (Khan et al. Immunity 1995 3:283;Ellmeier et al. J. Exp. Med. 2000 192:1611). Mutation of Btk in humansleads to the condition X-linked agammaglobulinemia (XLA) (reviewed inRosen et al. New Eng. J. Med. 1995 333:431 and Lindvall et al. Immunol.Rev. 2005 203:200). These patients are immunocompromised and showimpaired maturation of 13-cells, decreased immunoglobulin and peripheralB-cell levels, diminished T-cell independent immune responses as well asattenuated calcium mobilization following BCR stimulation.

Evidence for a role for Btk in autoimmune and inflammatory diseases hasalso been provided by Btk-deficient mouse models. In preclinical murinemodels of systemic lupus erythematosus (SLE), Btk-deficient mice showmarked amelioration of disease progression. In addition, Btk-deficientmice are resistant to collagen-induced arthritis (Jansson and HolmdahlClin. Exp. Immunol. 1993 94:459). A selective Btk inhibitor has beendemonstrated dose-dependent efficacy in a mouse arthritis model (Z. Panet al., Chem. Med Chem. 2007 2:58-61).

Btk is also expressed by cells other than B-cells that may be involvedin disease processes. For example, Btk is expressed by mast cells andBtk-deficient bone marrow derived mast cells demonstrate impairedantigen induced degranulation (Iwaki et. al. J. Biol. Chem. 2005280:40261). This shows Btk could be useful to treat pathological mastcells responses such as allergy and asthma. Also monocytes from XLApatients, in which Btk activity is absent, show decreased TNF alphaproduction following stimulation (Horwood et al. J Exp Med 197:1603,2003). Therefore TNF alpha mediated inflammation could be modulated bysmall molecular Btk inhibitors. Also, Btk has been reported to play arole in apoptosis (Islam and Smith Immunol. Rev. 2000 178:49,) and thusBtk inhibitors would be useful for the treatment of certain B-celllymphomas and leukemias (Feldhahn et al. J. Exp. Med. 2005 201:1837,).

SUMMARY OF THE INVENTION

The present application provides the Btk inhibitor compounds of FormulaeI-III, methods of use thereof, as described herein below:

The application provides a compound of Formula I,

-   wherein:-   R is H, —R¹, —R¹, —R²—R³, or —R²—R³;    -   R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is        optionally substituted with lower alkyl, hydroxy, lower alkoxy,        halo, nitro, amino, cyano, or halo-lower alkyl;    -   R² is —C(═O), —C(═O)O, —C(═O)NH, or —S(═O)₂;    -   R³ is H or R⁴;    -   R⁴ is lower alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl        heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl,        cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or        heterocycloalkyl alkyl, and is optionally substituted with lower        alkyl, hydroxy, lower alkoxy, halo, nitro, amino, cyano, or        halo-lower alkyl;-   X is CH or N;-   Y¹ is H or lower alkyl;-   each Y² is independently halogen or lower alkyl, wherein lower alkyl    is optionally substituted with one or more substituents selected    from the group consisting of hydroxy, lower alkoxy, and halogen;-   n is 0, 1, 2, or 3.-   Y³ is H, halogen, or lower alkyl, wherein lower alkyl is optionally    substituted with one or more substituents selected from the group    consisting of hydroxy, lower alkoxy, amino, and halogen;-   m is 0 or 1;-   Y⁴ is Y^(4a), Y^(4b), Y^(4c), or Y^(4d);    -   Y^(4a) is H or halogen;    -   Y^(4b) is lower alkyl, optionally substituted with one or more        substituents selected from the group consisting of lower        haloalkyl, halogen, hydroxy, amino, and lower alkoxy;    -   Y^(4c) is lower cycloalkyl, optionally substituted with one or        more substituents selected from the group consisting of lower        alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower        alkoxy; and    -   Y^(4d) is amino, optionally susbstituted with one or more lower        alkyl;-   or a pharmaceutically acceptable salt thereof.

In one variation of Formula I, Y¹ is methyl.

In one variation of Formula I, X is CH.

In one variation of Formula I, n is 1 and m is 0.

In one variation of Formula I, Y³ is H.

In one variation of Formula I, Y² is methyl.

In one variation of Formula I, Y² is hydroxymethyl.

In one variation of Formula I, Y² is hydroxyethyl.

In one variation of Formula I, Y² is halogen.

In one variation of Formula I, Y⁴ is

wherein, Y⁵ is halogen, lower alkyl or lower haloalkyl.

In one variation of Formula I, wherein Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

In one variation of Formula I, wherein Y⁴ is

wherein, Y⁵ and Y⁶ are independently H or lower alkyl.

In one variation of the above compound, wherein Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

In one variation of Formula I,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula I, R is —R¹—R²—R³;

-   R¹ is phenyl or pyridyl;-   R² is —C(═O),-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula I, R is —R¹—R²—R³;

-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula I, R is —R¹—R²—R³;

-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation, Formula I is:

In one variation, Formula I is:

In one variation, Formula I is:

The application provides a compound of Formula II,

-   wherein:-   R is H, —R¹, —R¹—R²—R³, or —R²—R³;    -   R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is        optionally substituted with lower alkyl, hydroxy, lower alkoxy,        halo, nitro, amino, cyano, or halo-lower alkyl;    -   R² is —C(═O), —C(═O)O, —C(═O)NH, or —S(═O)₂;    -   R³ is H or R⁴,    -   R⁴ is lower alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl        heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl,        cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or        heterocycloalkyl alkyl, and is optionally substituted with lower        alkyl, hydroxy, lower alkoxy, halo, nitro, amino, cyano, or        halo-lower alkyl;-   X is CH or N;-   Y¹ is H or lower alkyl;-   each Y² is independently halogen or lower alkyl, wherein lower alkyl    is optionally substituted with one or more substituents selected    from the group consisting of hydroxy, lower alkoxy, and halogen;-   n is 0, 1, 2, or 3.-   Y³ is halogen, or lower alkyl, wherein lower alkyl is optionally    substituted with one or more substituents selected from the group    consisting of hydroxy, lower alkoxy, amino, and halogen;-   m is 0 or 1;-   Y⁴ is Y^(4a), Y^(4b), Y^(4c), or Y^(4d);    -   Y^(4a) is H or halogen;    -   Y^(4b) is lower alkyl, optionally substituted with one or more        substituents selected from the group consisting of lower        haloalkyl, halogen, hydroxy, amino, and lower alkoxy;    -   Y^(4c) is lower cycloalkyl, optionally substituted with one or        more substituents selected from the group consisting of lower        alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower        alkoxy; and    -   Y^(4d) is amino, optionally susbstituted with one or more lower        alkyl;-   or a pharmaceutically acceptable salt thereof.

In one variation of Formula II Y¹ is methyl.

In one variation of Formula II, X is CH.

In one variation of the above compound, n is 1 and m is 0.

In one variation of Formula II, Y³ is H.

In one variation of Formula II, Y² is methyl.

In one variation of Formula II, Y² is hydroxymethyl.

In one variation of Formula II, Y² is hydroxyethyl.

In one variation of Formula II, Y² is halogen.

In one variation of Formula II, Y⁴ is

wherein, Y⁵ is halogen, lower alkyl, or lower haloalkyl.

In one variation of Formula II, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

In one variation of Formula II, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H or lower alkyl.

In one variation of Formula II, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower alkyl.

In one variation of Formula II,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula II,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula II,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula II,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation, Formula II is:

In one variation, Formula II is:

In one variation, Formula II is:

The application provides a compound of Formula III,

-   wherein:-   R is H, —R¹, —R¹—R²—R³, or —R²—R³;    -   R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is        optionally substituted with lower alkyl, hydroxy, lower alkoxy,        halo, nitro, amino, cyano, or halo-lower alkyl;    -   R² is —C(═O), —C(═O)O, —C(═O)NH, or —S(═O)₂;    -   R³ is H or R⁴;    -   R⁴ is lower alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl        heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl,        cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or        heterocycloalkyl alkyl, and is optionally substituted with lower        alkyl, hydroxy, lower alkoxy, halo, nitro, amino, cyano, or        halo-lower alkyl;-   X is CH or N;-   Y¹ is H or lower alkyl;-   each Y² is independently halogen or lower alkyl, wherein lower alkyl    is optionally substituted with one or more substituents selected    from the group consisting of hydroxy, lower alkoxy, and halogen;-   n is 0, 1, 2, or 3.-   Y³ is H, halogen, or lower alkyl, wherein lower alkyl is optionally    substituted with one or more substituents selected from the group    consisting of hydroxy, lower alkoxy, amino, and halogen;-   m is 0 or 1;-   Y⁴ is Y^(4a), Y^(4b), Y^(4c), or Y^(4d);    -   Y^(4a) is H or halogen;    -   Y^(4b) is lower alkyl, optionally substituted with one or more        substituents selected from the group consisting of lower        haloalkyl, halogen, hydroxy, amino, and lower alkoxy;    -   Y^(4c) is lower cycloalkyl, optionally substituted with one or        more substituents selected from the group consisting of lower        alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower        alkoxy; and    -   Y^(4d) is amino, optionally susbstituted with one or more lower        alkyl;-   or a pharmaceutically acceptable salt thereof.

In one variation of Formula III, Y¹ is methyl.

In one variation of Formula III, X is CH.

In one variation of Formula III, n is 1 and m is 0.

In one variation of Formula III, Y³ is H.

In one variation of Formula III, Y² is methyl.

In one variation of Formula III, Y² is hydroxymethyl.

In one variation of Formula III, Y² is hydroxyethyl.

In one variation of Formula III, Y² is halogen.

In one variation of Formula III, Y⁴ is

wherein, Y⁵ is halogen, lower alkyl, or lower haloalkyl.

In one variation of Formula III, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

In one variation of Formula III, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H or lower alkyl.

In one variation of Formula III, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

In one variation of Formula III,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula III,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl,-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula III,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula III,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation, Formula III is:

In one variation, Formula III is:

In one variation, Formula III is:

The application provides a compound of Formula I,

-   wherein:-   R is H, —R¹, —R¹—R²—R³, or —R²—R³;    -   R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is        optionally substituted with lower alkyl, hydroxy, lower alkoxy,        halo, nitro, amino, cyano, or halo-lower alkyl;    -   R² is —C(═O), —C(═O)O, —C(═O)NH, or —S(═O)₂;    -   R³ is H or R⁴;    -   R⁴ is lower alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl        heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl,        cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or        heterocycloalkyl alkyl, and is optionally substituted with lower        alkyl, hydroxy, lower alkoxy, halo, nitro, amino, cyano, or        halo-lower alkyl;-   X is CH or N;-   Y¹ is H or lower alkyl;-   each Y² is independently halogen or lower alkyl, wherein lower alkyl    is optionally substituted with one or more substituents selected    from the group consisting of hydroxy, lower alkoxy, and halogen;-   n is 0, 1, 2, or 3.-   Y³ is H, halogen, or lower alkyl, wherein lower alkyl is optionally    substituted with one or more substituents selected from the group    consisting of hydroxy, lower alkoxy, amino, and halogen;-   m is 0 or 1;-   Y⁴ is Y^(4a), Y^(4b), Y^(4c), or Y^(4d);    -   Y⁴a is H or halogen;    -   Y^(4b) is lower alkyl, optionally substituted with one or more        substituents selected from the group consisting of lower        haloalkyl, halogen, hydroxy, amino, and lower alkoxy;    -   Y^(4c) is lower cycloalkyl, optionally substituted with one or        more substituents selected from the group consisting of lower        alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower        alkoxy; and    -   Y^(4d) is amino, optionally susbstituted with one or more lower        alkyl;-   or a pharmaceutically acceptable salt thereof.

The application also provides a compound of Formula I,

-   wherein:-   R is H, —R¹, —R¹—R²—R³, —R¹—R³, or —R²—R³;    -   R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is        optionally substituted with one or more lower alkyl, hydroxy,        hydroxy lower alkyl, lower alkoxy, halo, nitro, amino, amido,        cyano, oxo, or halo-lower alkyl;    -   R² is —C(═O), —C(═O)O, —C(═O)NR^(2′), —NHC(═O)O, —C(═NH)NR^(2′),        or —S(═O)₂;        -   R^(2′) is H or lower alkyl;    -   R³ is H or R⁴;    -   R⁴ is lower alkyl, amino, aryl, arylalkyl, alkylaryl,        heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl,        alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl        heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally        substituted with one or more lower alkyl, hydroxy, lower alkoxy,        hydroxy lower alkyl, hydroxy lower alkoxy, lower alkyl sulfonyl,        lower alkyl sulfonamido, carbamate, carboxy, ester, amido, acyl,        halo, nitro, amino, cyano, oxo, or halo-lower alkyl;-   X is CH or N;-   Y¹ is H, lower alkyl, or lower haloalkyl;-   each Y² is independently halogen, oxime, or lower alkyl, wherein    lower alkyl is optionally substituted with one or more substituents    selected from the group consisting of hydroxy, lower alkoxy, lower    haloalkoxy, lower haloalkyl, carboxy, amino, and halogen;-   n is 0, 1, 2, or 3.-   Y³ is H, halogen, or lower alkyl, wherein lower alkyl is optionally    substituted with one or more substituents selected from the group    consisting of hydroxy, lower alkoxy, amino, and halogen;-   m is 0 or 1;-   Y⁴ is Y^(4a), Y^(4b), Y^(4c), Y^(4d); or    -   Y^(4a) is H or halogen;    -   Y^(4b) is lower alkyl, optionally substituted with one or more        substituents selected from the group consisting of lower        haloalkyl, halogen, hydroxy, amino, cyano, and lower alkoxy;    -   Y^(4c) is lower cycloalkyl, optionally substituted with one or        more substituents selected from the group consisting of lower        alkyl, lower haloalkyl, halogen, hydroxy, amino, cyano, and        lower alkoxy; and    -   Y^(4d) is amino, optionally susbstituted with one or more lower        alkyl, alkoxy lower alkyl, or hydroxy lower alkyl;-   or a pharmaceutically acceptable salt thereof.

In one variation of Formula I, Y¹ is methyl.

In one variation of Formula I, X is CH.

In one variation of Formula I, n is 1 and m is 0.

In one variation of Formula I, Y³ is H.

In one variation of Formula I, Y² is methyl.

In one variation of Formula I, Y² is hydroxymethyl.

In one variation of Formula I, Y² is hydroxyethyl.

In one variation of Formula I, Y² is halogen.

In one variation of Formula I, Y⁴ is

wherein, Y⁵ is halogen, lower alkyl or lower haloalkyl.

In one variation of Formula I, wherein Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

In one variation of Formula I, wherein Y⁴ is

wherein, Y⁵ and Y⁶ are independently H or lower alkyl.

In one variation of the above compound, wherein Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

In one variation of Formula I,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula I, R is —R¹—R²—R³;

-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula I, R is —R¹—R²—R³;

-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula I, R is —R¹—R²—R³;

-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation, Formula I is:

In one variation, Formula I is:

In one variation, Formula I is:

The application also provides a compound of Formula I, wherein Formula Iis selected from the group consisting of:

-   6-Dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   1-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-3-ethyl-urea;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   2-(2-Difluoromethoxy-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-ylmethyl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-methylamino-3,4-dihydro-2H-isoquinolin-1-one;-   2-{3-[5-(1-tert-Butyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-6-cyclopropyl-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-{3-[5-(1-ethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   2-{3-[5-(1-Cyclohexyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-6-cyclopropyl-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-6-oxo-5-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-ylamino]-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-{3-[5-(1-cyclopropyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-{2-hydroxymethyl-3-[5-(2-isopropyl-2H-[1,2,3]triazol-4-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-{2-hydroxymethyl-3-[5-(1-isopropyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-(1-Fluoro-cyclopropyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-(Ethyl-methyl-amino)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-tert-Butyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-(1-Difluoromethyl-cyclopropyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-tert-Butyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(4-methyl-piperazin-1-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   2-(3-{5-[5-(4,4-Difluoro-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(2-oxa-6-aza-spiro[3.3]heptane-6-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(4-methyl-piperazin-1-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(3-{5-[5-(1,1-dioxo-1λ⁶-thiomorpholine-4-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{5-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;    6-Dimethylamino-2-{3-[5-(5-ethoxymethyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[5-(2-methoxy-ethoxymethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(3-{5-[5-(2-hydroxy-ethoxymethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(3-{5-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[5-(5-methanesulfonylmethyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-6-oxo-5-[5-(2-oxo-pyrrolidin-1-ylmethyl)-pyridin-2-ylamino]-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinoln-1-one;-   6-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-N-(2-methoxy-ethyl)-N-methyl-nicotinamide;-   2-(3-{5-[5-(4,4-Difluoro-piperidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(3-{5-[1-(2-hydroxy-3-methoxy-propyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-3-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-[3-(5-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-hydroxymethyl-phenyl]-3,4-dihydro-2H-isoquinolin-1-one;-   2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-(1-methyl-cyclopropyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(3-{5-[5-(4-ethoxy-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[5-(4-methoxymethyl-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   2-(3-{5-[5-(Azetidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;-   2-(3-{5-[5-(3,3-Difluoro-azetidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(3-{5-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-tert-Butyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-tert-Butyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(2-oxa-6-aza-spiro[3.3]heptane-6-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(3-{5-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(3-{5-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   N-(6-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-ylmethyl)-methanesulfonamide;-   (6-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-ylmethyl)-carbamic    acid methyl ester;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(2-oxa-6-aza-spiro[3.3]heptane-6-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(3-{5-[5-(1,1-dioxo-1λ⁶-thiomorpholine-4-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-(Ethyl-methyl-amino)-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(3-{5-[1-(2-dimethylamino-ethyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-(1-Hydroxy-1-methyl-ethyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-[(2-Hydroxy-ethyl)-methyl-amino]-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-[3-(5-{5-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-2-ylamino}-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-hydroxymethyl-phenyl]-3,4-dihydro-2H-isoquinoln-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[5-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-1,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(3-{5-[5-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   2-(3-{5-[5-(3,3-Difluoro-azetidin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(3-{5-[5-(3-hydroxy-azetidin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   2-{3-[5-(5-Diethylamino-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;    -   2-{2-Hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-6-(1-methyl-cyclopropyl)-3,4-dihydro-2H-isoquinolin-1-one;-   2-{3-[5-(4,4-Difluoro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[5-(1-methanesulfonylmethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(2-propyl-2H-[1,2,3]triazol-4-ylamino)-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-6-oxo-5-[5-(2-oxo-pyrrolidin-1-yl)-pyridin-2-ylamino]-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6′-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-3,4,5,6-tetrahydro-[1,3′]bipyridinyl-2-one;-   6-Dimethylamino-2-(3-{5-[5-(1,1-dioxo-1λ⁶-[1,2]thiazinan-2-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(3-{5-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   2-(6-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yloxy)-acetamide;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;    1-(6-{5-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridine-3-carbonyl)-piperidine-4-carbonitrile;-   6-Cyclopropyl-2-(3-{5-[5-(3-ethoxy-pyrrolidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[5-(3-methanesulfonyl-propoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(3-{5-[5-(2-hydroxy-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinoln-1-one;-   2-(3-{5-[5-(4-Acetyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;-   1-(6-{5-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridine-3-carbonyl)-piperidine-3-carbonitrile;-   2-(2-acetaldehyde    oxime-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one-   2-[6-(1-Chloro-cyclopropyl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde;-   6-(1-Chloro-cyclopropyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   2-[2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrile;-   6-(1-Chloro-cyclopropyl)-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one-   6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   1-(2-{2-Hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-cyclopropanecarbonitrile;-   2-(2-{2-Hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-2-methyl-propionitrile;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-piperazin-1-yl-pyridin-2-ylamino)-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[5-(5-hydroxymethyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(6-morpholin-4-yl-pyrimidin-4-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(5-methyl-isoxazol-3-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[5-(isoxazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-(1-Chloro-cyclopropyl)-2-[3-(5-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-hydroxymethyl-phenyl]-3,4-dihydro-2H-isoquinolin-1-one;-   1-[2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-cyclopropanecarbonitrile;-   2-(6-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yloxy)-N,N-dimethyl-acetamide;-   6-(1-Hydroxy-1-methyl-ethyl)-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[5-(2-hydroxy-propoxymethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   (2-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-4-yl)-carbamic    acid benzyl ester;-   2-{3-[5-(4-Amino-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;-   N-(2-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-4-yl)-acetamide;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(4-methyl-piperazin-1-yl)-pyrimidin-4-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-[(2-Hydroxy-ethyl)-methyl-amino]-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   2-(3-{1-Difluoromethyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[5-(2-methoxy-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   2-(3-{5-[5-(3,3-Difluoro-azetidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(3-{5-[5-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   1-(5-{3-[6-(1-Chloro-cyclopropyl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-2-hydroxymethyl-phenyl}-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-3-ethyl-urea;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-trifluoromethyl-isoxazol-3-ylamino)-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   1-{5-[3-(6-tert-Butyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-3-methyl-urea;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[5-(3-hydroxy-3-methyl-azetidin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-(1-Chloro-cyclopropyl)-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   2-(3-{5-[5-(4-Acetyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-(1-chloro-cyclopropyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-(1-Chloro-cyclopropyl)-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-piperazin-1-yl-pyridin-2-ylamino)-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   1-{5-[3-(6-tert-Butyl-1-oxo-3,4-dihydro-1H-isoquinoln-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-3-ethyl-urea;-   6-[Bis-(2-hydroxy-ethyl)-amino]-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   2-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzoic    acid;-   6-Dimethylamino-2-{5-fluoro-2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   1-(6-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-pyrrolidine-3-carboxylic    acid methyl ester;-   1-(6-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-pyrrolidine-3-carboxylic    acid;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[6-(2-methoxy-1-methyl-ethylamino)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[5-(1H-imidazol-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   N-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-N′-carboxylic    acid butyl ester-guanidine-   N-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-guanidine;-   2-(2-Aminomethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-dimethylaminomethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   1-(5-{2-Hydroxymethyl-3-[6-(1-hydroxy-1-methyl-ethyl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-3-methyl-urea;-   1-(5-{3-[6-(2-Cyano-1,1-dimethyl-ethyl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-2-hydroxymethyl-phenyl}-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-3-methyl-urea;-   2-[2-Hydroxymethyl-3-(5-{5-[4-(2-methoxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-6-(1-methyl-cyclopropyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[6-((R)-3-hydroxy-pyrrolidin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{3-[5-(5-ethyl-isoxazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Azetidin-1-yl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   1-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-4-fluoro-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-3-methyl-urea;-   6-tert-Butyl-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-piperazin-1-yl-pyridin-2-ylamino)-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   2-Cyano-N-{5-[3-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-acetamide;-   6-[2-(2-Hydroxy-ethoxy)-1,1-dimethyl-ethyl]-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-(1-Chloro-cyclopropyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one-   6-(1-Hydroxy-1-methyl-ethyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   6-(2-Hydroxy-1,1-dimethyl-ethyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;-   2-[2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrile-   N-{5-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-3-oxo-butyramide;-   6-Dimethylamino-2-[2-hydroxymethyl-3-(5-{5-[(2-methoxy-ethylamino)-methyl]-pyridin-2-ylamino}-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-3,4-dihydro-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{3-[5-(5-ethyl-4-oxo-4,5-dihydro-1H-imidazol-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   1-{5-[3-(6-tert-Butyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-3-(3-dimethylamino-propyl)-urea;-   6-Dimethylamino-2-{3-[5-(5-ethyl-1H-imidazol-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-3,4-dihydro-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one;    and-   6-Cyclopropyl-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one.

The application provides a compound of Formula II,

-   wherein:-   R is H, —R¹, —R¹—R²—R³, or —R²—R³;    -   R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is        optionally substituted with lower alkyl, hydroxy, lower alkoxy,        halo, nitro, amino, cyano, or halo-lower alkyl;    -   R² is —C(═O), —C(═O)O, —C(═O)NH, or —S(═O)₂;    -   R³ is H or R⁴;    -   R⁴ is lower alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl        heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl,        cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or        heterocycloalkyl alkyl, and is optionally substituted with lower        alkyl, hydroxy, lower alkoxy, halo, nitro, amino, cyano, or        halo-lower alkyl;-   X is CH or N,-   Y¹ is H or lower alkyl;-   each Y² is independently halogen or lower alkyl, wherein lower alkyl    is optionally substituted with one or more substituents selected    from the group consisting of hydroxy, lower alkoxy, and halogen;-   n is 0, 1, 2, or 3.-   Y³ is H, halogen, or lower alkyl, wherein lower alkyl is optionally    substituted with one or more substituents selected from the group    consisting of hydroxy, lower alkoxy, amino, and halogen;-   m is 0 or 1;-   Y⁴ is Y^(4a), Y^(4b), Y^(4c), or Y^(4d);    -   Y^(4a) is H or halogen;    -   Y^(4b) is lower alkyl, optionally substituted with one or more        substituents selected from the group consisting of lower        haloalkyl, halogen, hydroxy, amino, and lower alkoxy;    -   Y^(4c) is lower cycloalkyl, optionally substituted with one or        more substituents selected from the group consisting of lower        alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower        alkoxy; and    -   Y^(4d) is amino, optionally susbstituted with one or more lower        alkyl;-   or a pharmaceutically acceptable salt thereof.

The application also provides a compound of Formula II,

-   wherein:-   R is H, —R¹, —R¹—R²—R³, —R¹—R³, or —R²—R³;    -   R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is        optionally substituted with one or more lower alkyl, hydroxy,        hydroxy lower alkyl, lower alkoxy, halo, nitro, amino, amido,        cyano, oxo, or halo-lower alkyl;    -   R² is —C(═O), —C(═O)O, —C(═O)NR^(2′), or —S(═O)₂;        -   R² is H or lower alkyl;    -   R³ is H or R⁴;    -   R⁴ is lower alkyl, amino, aryl, arylalkyl, alkylaryl,        heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl,        alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl        heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally        substituted with one or more lower alkyl, hydroxy, hydroxy lower        alkyl, lower alkoxy, halo, nitro, amino, cyano, or halo-lower        alkyl;-   X is CH or N;-   Y¹ is H, lower alkyl, or lower haloalkyl;-   each Y² is independently halogen or lower alkyl, wherein lower alkyl    is optionally substituted with one or more substituents selected    from the group consisting of hydroxy, lower alkoxy, lower    haloalkoxy, lower haloalkyl, carboxy, amino, and halogen;-   n is 0, 1, 2, or 3.-   Y³ is H, halogen, or lower alkyl, wherein lower alkyl is optionally    substituted with one or more substituents selected from the group    consisting of hydroxy, lower alkoxy, amino, and halogen;-   m is 0 or 1;-   Y⁴ is Y^(4a), Y^(4b), Y^(4c), or Y^(4d);    -   Y^(4a) is H or halogen;    -   Y^(4b) is lower alkyl, optionally substituted with one or more        substituents selected from the group consisting of lower        haloalkyl, halogen, hydroxy, amino, cyano, and lower alkoxy;    -   Y^(4c) is lower cycloalkyl, optionally substituted with one or        more substituents selected from the group consisting of lower        alkyl, lower haloalkyl, halogen, hydroxy, amino, cyano, and        lower alkoxy; and    -   Y^(4d) is amino, optionally susbstituted with one or more lower        alkyl, alkoxy lower alkyl, or hydroxy lower alkyl;-   or a pharmaceutically acceptable salt thereof.

In one variation of Formula II, Y¹ is methyl.

In one variation of Formula II, X is CH.

In one variation of the above compound, n is 1 and m is 0.

In one variation of Formula II, Y³ is H.

In one variation of Formula II, Y² is methyl.

In one variation of Formula II, Y² is hydroxymethyl.

In one variation of Formula II, Y² is hydroxyethyl.

In one variation of Formula II, Y² is halogen.

In one variation of Formula II, Y⁴ is

wherein, Y⁵ is halogen, lower alkyl, or lower haloalkyl.

In one variation of Formula II, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

In one variation of Formula II, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H or lower alkyl.

In one variation of Formula II, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower alkyl.

In one variation of Formula II,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula II,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula II,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula II,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation, Formula II is:

In one variation, Formula II is:

In one variation, Formula II is:

The application also provides a compound of Formula II, wherein FormulaII is selected from the group consisting of:

-   7-tert-Butyl-3-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1H-quinolin-4-one;    and-   7-Dimethylamino-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1H-quinolin-4-one.

The application provides a compound of Formula III,

-   wherein:-   R is H, —R¹, —R¹—R²—R³, or —R²—R³;    -   R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is        optionally substituted with lower alkyl, hydroxy, lower alkoxy,        halo, nitro, amino, cyano, or halo-lower alkyl;    -   R² is —C(═O), —C(═O)O, —C(═O)NH, or —S(═O)₂;    -   R³ is H or R⁴;    -   R⁴ is lower alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl        heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl,        cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or        heterocycloalkyl alkyl, and is optionally substituted with lower        alkyl, hydroxy, lower alkoxy, halo, nitro, amino, cyano, or        halo-lower alkyl;-   X is CH or N;-   Y¹ is H or lower alkyl;-   each Y² is independently halogen or lower alkyl, wherein lower alkyl    is optionally substituted with one or more substituents selected    from the group consisting of hydroxy, lower alkoxy, and halogen;-   n is 0, 1, 2, or 3.-   Y³ is H, halogen, or lower alkyl, wherein lower alkyl is optionally    substituted with one or more substituents selected from the group    consisting of hydroxy, lower alkoxy, amino, and halogen;-   m is 0 or 1;-   Y⁴ is Y^(4a), Y^(4b), Y^(4c), or Y^(4d);    -   Y^(4a) is H or halogen;    -   Y^(4b) is lower alkyl, optionally substituted with one or more        substituents selected from the group consisting of lower        haloalkyl, halogen, hydroxy, amino, and lower alkoxy;    -   Y^(4c) is lower cycloalkyl, optionally substituted with one or        more substituents selected from the group consisting of lower        alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower        alkoxy; and    -   Y^(4d) is amino, optionally susbstituted with one or more lower        alkyl;-   or a pharmaceutically acceptable salt thereof.

The application also provides a compound of Formula III,

-   wherein:-   R is H, —R¹, —R¹—R²—R³, —R¹—R³, or —R²—R³;    -   R¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is        optionally substituted with one or more lower alkyl, hydroxy,        hydroxy lower alkyl, lower alkoxy, halo, nitro, amino, amido,        cyano, oxo, or halo-lower alkyl;    -   R² is —C(═O), —O, —C(═O)O, —C(═O)NR^(2′), or —S(═O)₂;        -   R^(2′) is H or lower alkyl;    -   R³ is H or R⁴;    -   R⁴ is lower alkyl, amino, aryl, arylalkyl, alkylaryl,        heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl,        alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl        heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally        substituted with one or more lower alkyl, hydroxy, hydroxy lower        alkyl, lower alkoxy, halo, nitro, amino, amido, acyl, cyano, or        halo-lower alkyl;-   X is CH or N;-   Y¹ is H, lower alkyl, or lower haloalkyl;-   each Y² is independently halogen or lower alkyl, wherein lower alkyl    is optionally substituted with one or more substituents selected    from the group consisting of hydroxy, lower alkoxy, lower    haloalkoxy, lower haloalkyl, carboxy, amino, and halogen;-   n is 0, 1, 2, or 3.-   Y³ is H, halogen, or lower alkyl, wherein lower alkyl is optionally    substituted with one or more substituents selected from the group    consisting of hydroxy, lower alkoxy, amino, and halogen;-   m is 0 or 1;-   Y⁴ is Y^(4a), Y^(4b), Y^(4c), or Y^(4d);    -   Y^(4a) is H or halogen;    -   Y^(4b) is lower alkyl, optionally substituted with one or more        substituents selected from the group consisting of haloalkyl,        halogen, hydroxy, amino, cyano, and lower alkoxy;    -   Y^(4c) is lower cycloalkyl, optionally substituted with one or        more substituents selected from the group consisting of lower        alkyl, lower haloalkyl, halogen, hydroxy, hydroxy lower alkyl,        amino, cyano, and lower alkoxy; and    -   Y^(4d) is amino, optionally susbstituted with one or more lower        alkyl, alkoxy lower alkyl, or hydroxy lower alkyl;-   or a pharmaceutically acceptable salt thereof.

In one variation of Formula III, Y¹ is methyl.

In one variation of Formula III, X is CH.

In one variation of Formula III, n is 1 and m is 0.

In one variation of Formula III, Y³ is H.

In one variation of Formula III, Y² is methyl.

In one variation of Formula III, Y² is hydroxymethyl.

In one variation of Formula III, Y² is hydroxyethyl.

In one variation of Formula III, Y² is halogen.

In one variation of Formula III, Y⁴ is

wherein, Y⁵ is halogen, lower alkyl, or lower haloalkyl.

In one variation of Formula III, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

In one variation of Formula III, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H or lower alkyl.

In one variation of Formula III, Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.

In one variation of Formula III,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation or Formula III,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula III,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation of Formula III,

-   R is —R¹—R²—R³;-   R¹ is phenyl or pyridyl;-   R² is —C(═O);-   R³ is R⁴; and-   R⁴ is morpholine or piperazine, optionally substituted with one or    more lower alkyl.

In one variation, Formula III is:

In one variation, Formula III is:

In one variation, Formula III is:

The application also provides a compound of Formula III, wherein FormulaIII is selected from the group consisting of:

-   6-Dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;-   1-{5-[3-(6-Dimethylamino-1-oxo-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-3-ethyl-urea;-   2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-(1-methyl-cyclopropyl)-2H-isoquinolin-1-one;-   2-{2-Hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-ylmethyl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-6-(1-methyl-cyclopropyl)-2H-isoquinolin-1-one;-   2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-(1-methyl-cyclopropyl)-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-ylmethyl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3-methyl-2H-isoquinolin-1-one;-   2-{2-Hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-6-(1-methyl-cyclopropyl)-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;-   6-tert-Butyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;-   6-Cyclopropyl-3-hydroxymethyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;-   6-Cyclopropyl-3-hydroxymethyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;-   6-Cyclopropyl-3-dimethylaminomethyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;-   3-tert-Butoxymethyl-6-cyclopropyl-2-{3-[5-(6-fluoro-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(6-methylamino-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;-   2-{3-[5-(6-Amino-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-6-dimethylamino-2H-isoquinolin-1-one;-   2-(6-{5-[3-(6-Dimethylamino-1-oxo-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yloxy)-N-methyl-acetamide;-   2-{3-[5-(5,6-Dimethoxy-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-6-dimethylamino-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[5-methoxy-6-(2-methoxy-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[6-methoxy-5-(2-methoxy-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;-   2-(3-{5-[5,6-Bis-(2-methoxy-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(2-morpholin-4-yl-pyrimidin-4-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;-   2-[4-(6-{5-[3-(6-Dimethylamino-1-oxo-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-piperazin-1-yl]-isobutyramide;-   2-(3-{5-[6-(4-Acetyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-2H-isoquinolin-1-one;-   6-Dimethylamino-2-{3-[5-(5-ethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-2H-isoquinolin-1-one;-   6-Dimethylamino-2-(3-{5-[5-(2-hydroxy-ethoxy)-6-(2-methoxy-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-2H-isoquinolin-1-one;-   6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-isoquinolin-1-one;    and-   2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-6-(1-methyl-cyclopropyl)-2H-isoquinolin-1-one.

The application provides a method for treating an inflammatory and/orautoimmune condition comprising administering to a patient in needthereof a therapeutically effective amount of the Btk inhibitor compoundof any one of the above Formulae or variations thereof.

The application provides a method for treating an arthritis comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the Btk inhibitor compound of any one of the above Formulae orvariations thereof.

The application provides a method of inhibiting B-cell proliferationcomprising administering to a patient in need thereof a therapeuticallyeffective amount of the Btk inhibitor compound of any one of the aboveFormulae or variations thereof.

The application provides a method for inhibiting Btk activity comprisingadministering the Btk inhibitor compound of any one of the aboveFormulae or variations thereof, wherein the Btk inhibitor compoundexhibits an IC₅₀ of 50 micromolar or less in an in vitro biochemicalassay of Btk activity.

In one variation of the above method, the Btk inhibitor compoundexhibits an IC₅₀ of 100 nanomolar or less in an in vitro biochemicalassay of Btk activity.

In one variation of the above method, the compound exhibits an IC₅₀ of10 nanomolar or less in an in vitro biochemical assay of Btk activity.

The application provides a method for treating an inflammatory conditioncomprising co-administering to a patient in need thereof atherapeutically effective amount of an anti-inflammatory compound incombination with the Btk inhibitor compound of any one of the aboveFormulae or variations thereof.

The application provides a method for treating arthritis comprisingco-administering to a patient in need thereof a therapeuticallyeffective amount of an anti-inflammatory compound in combination withthe Btk inhibitor compound of any one of the above Formulae orvariations thereof.

The application provides a method for treating a lymphoma or a BCR-ABL1⁺leukemia cells by administering to a patient in need thereof atherapeutically effective amount of the Btk inhibitor compound of anyone of the above Formulae or variations thereof.

The application provides a pharmaceutical composition comprising the Btkinhibitor compound of any one of the above Formulae or variationsthereof, admixed with at least one pharmaceutically acceptable carrier,excipient or diluent.

DETAILED DESCRIPTION OF THE INVENTION

The present application provides compounds of generic Formulae I-III,wherein variables R, X, Y¹, Y², Y³, Y⁴, n, and m are as defined hereinabove.

In one embodiment of the present invention, there is provided a compoundaccording to generic Formula I which comprises the exemplified Btkinhibitor compounds of Formulae I-1 to I-155. In one embodiment of thepresent invention, there is provided a compound according to generic.Formula II which comprises the exemplified Btk inhibitor compounds ofFormulae II-1 and II-2. In one embodiment of the present invention,there is provided a compound according to generic Formula III whichcomprises the exemplified Btk inhibitor compounds of Formulae III-1 toIII-36.

The present application discloses 5-phenyl-1H-pyridin-2-one and6-phenyl-2H-pyridazin-3-one derivatives according to generic FormulaeI-III:

The phrase “as defined herein above” refers to the broadest definitionfor each group as provided in the Summary of the Invention or thebroadest claim. In all other aspects, variations and embodimentsprovided, substituents which can be present in each embodiment and whichare not explicitly defined retain the broadest definition provided inthe Summary of the Invention.

The compounds of generic Formulae I-III inhibit Bruton's tyrosine kinase(Btk). Activation of Btk by upstream kinases results in activation ofphospholipase-Cγ which, in turn, stimulates release of pro-inflammatorymediators. The compounds of generic Formulae I-III, incorporating sidechains of 1H-quinolin-4-one, 3,4-dihydro-2H-isoquinolin-1-one, and2H-isoquinolin-1-one on the 5-phenyl-1H-pyridin-2-one and6-phenyl-2H-pyridazin-3-one ring systems, exhibit unexpectedly enhancedinhibitory activity compared to analogues with other side chains.Compounds of Formulae I-III are useful in the treatment of arthritis andother anti-inflammatory and auto-immune diseases. Compounds according toFormulae I-III are, accordingly, useful for the treatment of arthritis.Compounds of Formulae I-III are useful for inhibiting Btk in cells andfor modulating B-cell development. The present invention furthercomprises pharmaceutical compositions containing compounds of FormulaeI-III admixed with pharmaceutically acceptable carrier, excipients ordiluents.

Definitions

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “as defined herein above” refers to the broadest definitionfor each group as provided in the Summary of the Invention or thebroadest claim. In all other embodiments provided below, substituentswhich can be present in each embodiment and which are not explicitlydefined retain the broadest definition provided in the Summary of theInvention.

As used in this specification, whether in a transitional phrase or inthe body of the claim, the terms “comprise(s)” and “comprising” are tobe interpreted as having an open-ended meaning. That is, the terms areto be interpreted synonymously with the phrases “having at least” or“including at least”. When used in the context of a process, the term“comprising” means that the process includes at least the recited steps,but may include additional steps. When used in the context of a compoundor composition, the term “comprising” means that the compound orcomposition includes at least the recited features or components, butmay also include additional features or components.

As used herein, unless specifically indicated otherwise, the word “or”is used in the “inclusive” sense of “and/or” and not the “exclusive”sense of “either/or”.

The term “independently” is used herein to indicate that a variable isapplied in any one instance without regard to the presence or absence ofa variable having that same or a different definition within the samecompound. Thus, in a compound in which R″ appears twice and is definedas “independently carbon or nitrogen”, both R″s can be carbon, both R″scan be nitrogen, or one R″ can be carbon and the other nitrogen.

When any variable occurs more than one time in any moiety or formuladepicting and describing compounds employed or claimed in the presentinvention, its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such compounds result in stablecompounds.

The symbols “*” at the end of a bond or

drawn through a bond each refer to the point of attachment of afunctional group or other chemical moiety to the rest of the molecule ofwhich it is a part. Thus, for example: MeC(═O)OR⁴ wherein

A bond drawn into ring system (as opposed to connected at a distinctvertex) indicates that the bond may be attached to any of the suitablering atoms

The term “optional” or “optionally” as used herein means that asubsequently described event or circumstance may, but need not, occur,and that the description includes instances where the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted” means that the optionally substituted moietymay incorporate a hydrogen or a substituent.

The phrase “optional bond” means that the bond may or may not bepresent, and that the description includes single, double, or triplebonds. If a substituent is designated to be a “bond” or “absent”, theatoms linked to the substituents are then directly connected.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 20%.

Certain compounds of formulae I-III may exhibit tautomerism. Tautomericcompounds can exist as two or more interconvertable species. Prototropictautomers result from the migration of a covalently bonded hydrogen atombetween two atoms. Tautomers generally exist in equilibrium and attemptsto isolate an individual tautomers usually produce a mixture whosechemical and physical properties are consistent with a mixture ofcompounds. The position of the equilibrium is dependent on chemicalfeatures within the molecule. For example, in many aliphatic aldehydesand ketones, such as acetaldehyde, the keto form predominates while; inphenols, the enol form predominates. Common prototropic tautomersinclude keto/enol (—C(═O)—CH—⇄—C(—OH)═CH—), amide/imidic acid(—C(═O)—N—⇄—C(—OH)═N—) and amidine (—C(═NR)—NH—⇄—C(—NHR)═N—) tautomers.The latter two are particularly common in heteroaryl and heterocyclicrings and the present invention encompasses all tautomeric forms of thecompounds.

Technical and scientific terms used herein have the meaning commonlyunderstood by one of skill in the art to which the present inventionpertains, unless otherwise defined. Reference is made herein to variousmethodologies and materials known to those of skill in the art. Standardreference works setting forth the general principles of pharmacologyinclude Goodman and Gilman's The Pharmacological Basis of Therapeutics,10^(th) Ed., McGraw Hill Companies Inc., New York (2001). Any suitablematerials and/or methods known to those of skill can be utilized incarrying out the present invention. However, preferred materials andmethods are described. Materials, reagents and the like to whichreference are made in the following description and examples areobtainable from commercial sources, unless otherwise noted.

The definitions described herein may be appended to formchemically-relevant combinations, such as “heteroalkylaryl,”“haloalkylheteroaryl,” “arylalkylheterocyclyl,” “alkylcarbonyl,”“alkoxyalkyl,” and the like. When the term “alkyl” is used as a suffixfollowing another term, as in “phenylalkyl,” or “hydroxyalkyl,” this isintended to refer to an alkyl group, as defined above, being substitutedwith one to two substituents selected from the other specifically-namedgroup. Thus, for example, “phenylalkyl” refers to an alkyl group havingone to two phenyl substituents, and thus includes benzyl, phenylethyl,and biphenyl. An “alkylaminoalkyl” is an alkyl group having one to twoalkylamino substituents. “Hydroxyalkyl” includes 2-hydroxyethyl,2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl,2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth.Accordingly, as used herein, the term “hydroxyalkyl” is used to define asubset of heteroalkyl groups defined below. The term -(ar)alkyl refersto either an unsubstituted alkyl or an aralkyl group. The term(hetero)aryl or (het)aryl refers to either an aryl or a heteroarylgroup.

The term “acyl” as used herein denotes a group of formula —C(═O)Rwherein R is hydrogen or lower alkyl as defined herein. The term or“alkylcarbonyl” as used herein denotes a group of formula C(═O)R whereinR is alkyl as defined herein. The term C₁₋₆ acyl refers to a group—C(═O)R contain 6 carbon atoms. The term “arylcarbonyl” as used hereinmeans a group of formula C(═O)R wherein R is an aryl group; the term“benzoyl” as used herein an “arylcarbonyl” group wherein R is phenyl.

The term “alkyl” as used herein denotes an unbranched or branched chain,saturated, monovalent hydrocarbon residue containing 1 to 10 carbonatoms. The term “lower alkyl” denotes a straight or branched chainhydrocarbon residue containing 1 to 6 carbon atoms. “C₁₋₁₀ alkyl” asused herein refers to an alkyl composed of 1 to 10 carbons. Examples ofalkyl groups include, but are not limited to, lower alkyl groups includemethyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, i-butyl or pentyl,isopentyl, neopentyl, hexyl, heptyl, and octyl.

When the term “alkyl” is used as a suffix following another term, as in“phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkylgroup, as defined above, being substituted with one to two substituentsselected from the other specifically-named group. Thus, for example,“phenylalkyl” denotes the radical R′R″—, wherein R′ is a phenyl radical,and R″ is an alkylene radical as defined herein with the understandingthat the attachment point of the phenylalkyl moiety will be on thealkylene radical. Examples of arylalkyl radicals include, but are notlimited to, benzyl, phenylethyl, 3-phenylpropyl. The terms “arylalkyl”or “aralkyl” are interpreted similarly except R′ is an aryl radical. Theterms “(het)arylalkyl” or “(het)aralkyl” are interpreted similarlyexcept R′ is optionally an aryl or a heteroaryl radical.

The terms “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refersto a straight or branched chain hydrocarbon residue containing 1 to 6carbon atoms wherein one or more carbon atoms are substituted with oneor more halogen atoms.

The term “alkylene” or “alkylenyl” as used herein denotes a divalentsaturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g.,(CH₂)_(n)) or a branched saturated divalent hydrocarbon radical of 2 to10 carbon atoms (e.g., —CHMe- or —CH₂CH(i-Pr)CH₂—), unless otherwiseindicated. Except in the case of methylene, the open valences of analkylene group are not attached to the same atom. Examples of alkyleneradicals include, but are not limited to, methylene, ethylene,propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene,2-ethylbutylene.

The term “alkoxy” as used herein means an —O-alkyl group, wherein alkylis as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy,n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy, including theirisomers. “Lower alkoxy” as used herein denotes an alkoxy group with a“lower alkyl” group as previously defined. “C₁₋₁₀ alkoxy” as used hereinrefers to an —O-alkyl wherein alkyl is C₁₋₁₀.

The term “hydroxyalkyl” as used herein denotes an alkyl radical asherein defined wherein one to three hydrogen atoms on different carbonatoms is/are replaced by hydroxyl groups.

The terms “alkylsulfonyl” and “arylsulfonyl” as used herein refers to agroup of formula —S(═O)₂R wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein. The term “heteroalkylsulfonyl” asused herein refers herein denotes a group of formula —S(═O)₂R wherein Ris “heteroalkyl” as defined herein.

The terms “alkylsulfonylamino” and “arylsulfonylamino”as used hereinrefers to a group of formula —NR′S(═O)₂R wherein R is alkyl or arylrespectively, R′ is hydrogen or C₁₋₃ alkyl, and alkyl and aryl are asdefined herein.

The term “cycloalkyl” as used herein refers to a saturated carbocyclicring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. “C₃₋₇ cycloalkyl” asused herein refers to an cycloalkyl composed of 3 to 7 carbons in thecarbocyclic ring.

The term carboxy-alkyl as used herein refers to an alkyl moiety whereinone, hydrogen atom has been replaced with a carboxyl with theunderstanding that the point of attachment of the heteroalkyl radical isthrough a carbon atom. The term “carboxy” or “carboxyl” refers to a—CO₂H moiety.

The term “heteroaryl” or “heteroaromatic” as used herein means amonocyclic or bicyclic radical of 5 to 12 ring atoms having at least onearomatic ring containing four to eight atoms per ring, incorporating oneor more N, O, or S heteroatoms, the remaining ring atoms being carbon,with the understanding that the attachment point of the heteroarylradical will be on an aromatic ring. As well known to those skilled inthe art, heteroaryl rings have less aromatic character than theirall-carbon counter parts. Thus, for the purposes of the invention, aheteroaryl group need only have some degree of aromatic character.Examples of heteroaryl moieties include monocyclic aromatic heterocycleshaving 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is notlimited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl,imidazolyl, oxazol, isoxazole, thiazole, isothiazole, triazoline,thiadiazole and oxadiaxoline which can optionally be substituted withone or more, preferably one or two substituents selected from hydroxy,cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, lowerhaloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino,dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro,alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples ofbicyclic moieties include, but are not limited to, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole,benzothiazole and benzisothiazole. Bicyclic moieties can be optionallysubstituted on either ring; however the point of attachment is on a ringcontaining a heteroatom.

The term “heterocyclyl”, “heterocycloalkyl” or “heterocycle” as usedherein denotes a monovalent saturated cyclic radical, consisting of oneor more rings, preferably one to two rings, including spirocyclic ringsystems, of three to eight atoms per ring, incorporating one or morering heteroatoms (chosen from N, O or S(O)₀₋₂), and which can optionallybe independently substituted with one or more, preferably one or twosubstituents selected from hydroxy, oxo, cyano, lower alkyl, loweralkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl,hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl,arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,aryl sulfonyl amino, alkyl aminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated.Examples of heterocyclic radicals include, but are not limited to,azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl,tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl,isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl,tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl.

Commonly used abbreviations include: acetyl (Ac),azo-bis-isobutyrylnitrile (AIBN), atmospheres (Atm),9-borabicyclo[3.3.1]nonane (9-BBN or BBN), tert-butoxycarbonyl (Boc),di-tert-butyl pyrocarbonate or boc anhydride (BOC₂O), benzyl (Bn), butyl(Bu), Chemical Abstracts Registration Number (CASRN), benzyloxycarbonyl(CBZ or Z), carbonyl diimidazole (CDI), 1,4-diazabicyclo[2.2.2]octane(DABCO), diethylaminosulfur trifluoride (DAST), dibenzylideneacetone(dba), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-dicyclohexylcarbodiimide(DCC), 1,2-dichloroethane (DCE), dichloromethane (DCM), diethylazodicarboxylate (DEAD), di-iso-propylazodicarboxylate (DIAD),di-iso-butylaluminumhydride (DIBAL or DIBAL-H), di-iso-propylethylamine(DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylaminopyridine(DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),1,1′-bis-(diphenylphosphino)ethane (dppe),1,1′-bis-(diphenylphosphino)ferrocene (dppf),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH),2-ethoxy-2H-quinoline-1-carboxylic acid ethyl ester (EEDQ), diethylether (Et₂O), O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate acetic acid (HATU), acetic acid (HOAc),1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography(HPLC), iso-propanol (IPA), lithium hexamethyl disilazane (LiHMDS),methanol (MeOH), melting point (mp), MeSO₂-(mesyl or Ms), methyl (Me),acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrum(ms), methyl t-butyl ether (MTBE), N-bromosuccinimide (NBS),N-carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine(NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), iso-propyl(i-Pr), pounds per square inch (psi), pyridine (pyr), room temperature(rt or RT), Cert-butyldimethylsilyl or t-BuMe₂Si (TBDMS), triethylamine(TEA or Et₃N), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), triflate orCF₃SO₂— (Tf), trifluoroacetic acid (TFA),1,1′-bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF),trimethylsilyl or Me₃Si (TMS), p-toluenesulfonic acid monohydrate (TsOHor pTsOH), 4-Me-C₆H₄SO₂— or tosyl (Ts), N-urethane-N-carboxyanhydride(UNCA), Conventional nomenclature including the prefixes normal (n), iso(i-), secondary (sec-), tertiary (tert-) and neo have their customarymeaning when used with an alkyl moiety. (J. Rigaudy and D. P. Klesney,Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.).

Compounds and Preparation

Examples of representative compounds encompassed by the presentinvention and within the scope of the invention are provided in thefollowing Table. These examples and preparations which follow areprovided to enable those skilled in the art to more clearly understandand to practice the present invention. They should not he considered aslimiting the scope of the invention, but merely as being illustrativeand representative thereof.

In general, the nomenclature used in this Application is based onAUTONOMTM v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. If there is a discrepancybetween a depicted structure and a name given that structure, thedepicted structure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it.

TABLE I depicts examples of pyridinone compounds according to genericFormulae I-III wherein X either is CH or N.

TABLE I Compound Structure Nomenclature (M + H)⁺ I-1 

6-Dimethylamino-2-(3- {1-methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one 579.2 I-2 

6-Dimethylamino-2-(2- hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one 609.1 I-3 

6-Dimethylamino-2-(2- methyl-3-{1-methyl-5- [5-(morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one 593.3 II-1

7-tert-Butyl-3-(3-{1- methyl-5-[5- (morpholine-4- carbonyl)-pyridin-2-ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}- phenyl)-1H-quinolin-4- one590.1 II-2

7-Dimethylamino-3-(2- methyl-3-{1-methyl-5- [5-(morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-1H-quinolin-4- one 591.1 III-1

6-Dimethylamino-2-(3- {1-methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin- 1-one 577.1 III-2

6-Dimethylamino-2-(2- methyl-3-{1-methyl-5- [5-(morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin- 1-one 591.1 III-3

6-Dimethylamino-2-(2- hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin- 1-one 607.2 I-4 

1-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-yl}-3-ethyl-urea I-5 

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-5-(1-methyl-1H-pyrazol-3-ylamino)-6- oxo-1,6-dihydro- pyridin-3-yl[-phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-6 

6-Cyclopropyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-7 

2-(2-Difluoromethoxy- 3-{1-methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-6- dimethylamino-3,4- dihydro-2H-isoquinolin- 1-one I-8 

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-5-(5-morpholin-4-ylmethyl-pyridin-2- ylamino)-6-oxo-1,6- dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro- 2H-isoquinolin-1-one I-9 

6-Dimethylamino-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(4-methyl-piperazine-1-carbonyl)- pyridin-2-ylamino]-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-10

2-(2-Hydroxymethyl-3- {1-methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-6-methylamino- 3,4-dihydro-2H- isoquinolin-1-one I-11

2-{3-[5-(1-tert-Butyl- 1H-pyrazol-3-ylamino)- 1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2- hydroxymethyl-phenyl}- 6-cyclopropyl-3,4-dihydro-2H-isoquinolin- 1-one I-12

6-Cyclopropyl-2-{3-[5- (1-ethyl-1H-pyrazol-3- ylamino)-1-methyl-6-oxo-1,6-dihydro- pyridin-3-yl]-2- hydroxymethyl-phenyl}- 3,4-dihydro-2H-isoquinolin-1-one I-13

2-{3-[5-(1-Cyclohexyl- 1H-pyrazol-3-ylamino)- 1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2- hydroxymethyl-phenyl}- 6-cyclopropyl-3,4-dihydro-2H-isoquinolin- 1-one I-14

6-Cyclopropyl-2-(2- hydroxymethyl-3-{1- methyl-6-oxo-5-[1-(2,2,2-trifluoro-ethyl)- 1H-pyrazol-3-ylamino]- 1,6-dihydro-pyridin-3-yl}-phenyl)-3,4- dihydro-2H-isoquinolin- 1-one I-15

6-Cyclopropyl-2-{3-[5- (1-cyclopropyl-1H- pyrazol-3-ylamino)-1-methyl-6-oxo-1,6- dihydro-pyridin-3-yl]-2- hydroxymethyl-phenyl}-3,4-dihydro-2H- isoquinolin-1-one I-16

6-Dimethylamino-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin- 2-ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-17

6-Cyclopropyl-2-{2- hydroxymethyl-3-[1- methyl-5-(1-methyl-1H-pyrazol-3-ylamino)-6- oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one I-18

6-Cyclopropyl-2-{2- hydroxymethyl-3-[5-(2- isopropyl-2H-[1,2,3]triazol-4- ylamino)-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl]-phenyl}- 3,4-dihydro-2H- isoquinolin-1-one I-19

6-Cyclopropyl-2-{2- hydroxymethyl-3-[5-(1- isopropyl-1H-pyrazol-3-ylamino)-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one I-20

6-(1-Fluoro - cyclopropyl)-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(morpholine-4- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-21

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one I-22

6-(Ethyl-methyl- amino)-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(morpholine-4- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-23

6-tert-Butyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-24

6-(1-Difluoromethyl- cyclopropyl)-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(morpholine-4- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-25

6-Cyclopropyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin- 2-ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-26

6-Fluoro-2-(2- hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-27

6-tert-Butyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin- 2-ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-28

6-Cyclopropyl-2-(2- hydroxymethyl-3-{1- methyl-5-[6-(4-methyl-piperazin-1-yl)- pyridazin-3-ylamino]-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-29

2-(3-{5-[5-(4,4- Difluoro-piperidine-1- carbonyl)-pyridin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl}-2-hydroxymethyl-phenyl)- 6-dimethylamino-3,4- dihydro-2H-isoquinolin-1-one I-30

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-5-(1-methyl-5-oxo-4,5-dihydro-1H- [1,2,4]triazol-3- ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]- phenyl}-3,4-dihydro- 2H-isoquinolin-1-one I-31

6-Dimethylamino-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(2-oxa-6-aza-spiro[3.3]heptane-6- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-32

6-Dimethylamino-2-(2- hydroxymethyl-3-{1- methyl-5-[6-(4-methyl-piperazin-1-yl)- pyridazin-3-ylamino]-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-33

6-Dimethylamino-2-(3- {5-[5-(1,1-dioxo-1λ⁶- thiomorpholine-4-carbonyl)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-2- hydroxymethyl-phenyl)- 3,4-dihydro-2H-isoquinolin-1-one I-34

6-Cyclopropyl-2-(2- hydroxymethyl-3-{5-[1- (2-hydroxy-2-methyl-propyl)-1H-pyrazol-3- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-35

6-Dimethylamino-2-{3- [5-(5-ethoxymethyl- pyridin-2-ylamino)-1-methyl-6-oxo-1,6- dihydro-pyridin-3-yl]-2- hydroxymethyl-phenyl}-3,4-dihydro-2H- isoquinolin-1-one I-36

6-Dimethylamino-2-(2- hydroxymethyl-3-{5-[5- (2-methoxy-ethoxymethyl)-pyridin- 2-ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-37

6-Dimethylamino-2-(3- {5-[5-(2-hydroxy- ethoxymethyl)-pyridin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl}-2-hydroxymethyl-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-38

6-Cyclopropyl-2-(3-{5- [1-(2-hydroxy-ethyl)- 1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6- dihydro-pyridin-3-yl}-2- hydroxymethyl-phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-39

6-Dimethylamino-2-{2- hydroxymethyl-3-[5-(5- methanesulfonylmethyl-pyridin-2-ylamino)-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro- 2H-isoquinolin-1-one I-40

6-Dimethylamino-2-(2- hydroxymethyl-3-{1- methyl-6-oxo-5-[5-(2-oxo-pyrrolidin-1- ylmethyl)-pyridin-2- ylamino]-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-41

6-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}-N-(2- methoxy-ethyl)-N- methyl-nicotinamide I-42

2-(3-{5-[5-(4,4- Difluoro-piperidin-1- ylmethyl)-pyridin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl}-2-hydroxymethyl-phenyl)- 6-dimethylamino-3,4- dihydro-2H-isoquinolin-1-one I-43

6-Cyclopropyl-2-(3-{5- [1-(2-hydroxy-3- methoxy-propyl)-1H-pyrazol-3-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-44

6-Cyclopropyl-2-(2- hydroxymethyl-3-{1- methyl-5-[1-(2-morpholin-4-yl-ethyl)- 1H-pyrazol-3-ylamino]- 6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-45

6-Dimethylamino-2-[3- (5-{5-[4-(2-hydroxy- ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl)-2-hydroxymethyl-phenyl]- 3,4-dihydro-2H- isoquinolin-1-one I-46

2-(2-Hydroxymethyl-3- {1-methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-6-(1-methyl- cyclopropyl)-3,4- dihydro-2H-isoquinolin- 1-oneI-47

6-Dimethylamino-2-(3- {5-[5-(4-ethoxy- piperidine-1-carbonyl)-pyridin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-48

6-Dimethylamino-2-(2- hydroxymethyl-3-{5-[5- (4-methoxymethyl-piperidine-1-carbonyl)- pyridin-2-ylamino]-1- methyl-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-49

2-(3-{5-[5-(Azetidine- 1-carbonyl)-pyridin-2- ylamino]-1-methyl-6-oxo-1,6-dihydro- pyridin-3-yl}-2- hydroxymethyl-phenyl)-6-dimethylamino-3,4- dihydro-2H-isoquinolin- 1-one I-50

2-(3-{5-[5-(3,3- Difluoro-azetidine-1- carbonyl)-pyridin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl}-2-hydroxymethyl-phenyl)- 6-dimethylamino-3,4- dihydro-2H-isoquinolin-1-one I-51

6-Dimethylamino-2-(3- {5-[5-(1,1-dioxo-1λ⁶- isothiazolidin-2-ylmethyl)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-2- hydroxymethyl-phenyl)- 3,4-dihydro-2H-isoquinolin-1-one I-52

6-tert-Butyl-2-{2- hydroxymethyl-3-[1- methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one I-53

6-tert-Butyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(2-oxa-6-aza-spiro[3.3]heptane-6- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-54

6-Dimethylamino-2-(3- {5-[5-(4-ethyl- piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl}-2-hydroxymethyl-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-55

6-Dimethylamino-2-(3- {5-[5-(4-ethyl- piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl}-2-hydroxymethyl-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-56

6-Dimethylamino-2-(2- hydroxymethyl-3-{5-[5- (4-hydroxy-4-methyl-piperidine-1-carbonyl)- pyridin-2-ylamino]-1- methyl-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-57

N-(6-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}-pyridin-3- ylmethyl)- methanesulfonamide I-58

(6-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}-pyridin-3- ylmethyl)-carbamic acid methyl ester I-59

6-Cyclopropyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(2-oxa-6-aza-spiro[3.3]heptane-6- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-60

6-Cyclopropyl-2-(3-{5- [5-(1,1-dioxo-1λ⁶- thiomorpholine-4-carbonyl)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-2- hydroxymethyl-phenyl)- 3,4-dihydro-2H-isoquinolin-1-one I-61

6-(Ethyl-methyl- amino)-2-{2- hydroxymethyl-3-[1- methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one I-62

6-Cyclopropyl-2-(3-{5- [1-(2-dimethylamino- ethyl)-1H-pyrazol-3-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl}-2-hydroxymethyl-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-63

6-(1-Hydroxy-1- methyl-ethyl)-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(morpholine-4- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-64

6-[(2-Hydroxy-ethyl)- methyl-amino]-2-(2- hydroxymethyl-3-{1-methyl-5-[5- (morpholine-4- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-65

6-Dimethylamino-2-[3- (5-{5-[(2-hydroxy- ethyl)-methyl-amino]-pyridin-2-ylamino}-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl)-2-hydroxymethyl-phenyl]- 3,4-dihydro-2H- isoquinolin-1-one I-66

6-Dimethylamino-2-{2- hydroxymethyl-3-[5-(4- hydroxy-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-6′- ylamino)-1-methyl-6-oxo-1,6-dihydro- pyridin-3-yl]-phenyl}- 3,4-dihydro-2H-isoquinolin-1-one I-67

6-Dimethylamino-2-(3- {5-[5-(1,1-dioxo-1λ⁶- thiomorpholin-4-yl)-pyridin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-68

2-(3-{5-[5-(3,3- Difluoro-azetidin-1-yl)- pyridin-2-ylamino]-1-methyl-6-oxo-1,6- dihydro-pyridin-3-yl}-2- hydroxymethyl-phenyl)-6-dimethylamino-3,4- dihydro-2H-isoquinolin- 1-one I-69

6-Dimethylamino-2-(3- {5-[5-(3-hydroxy- azetidin-1-yl)-pyridin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl}-2-hydroxymethyl-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-70

2-{3-[5-(5- Diethylamino-pyridin-2- ylamino)-1-methyl-6-oxo-1,6-dihydro- pyridin-3-yl]-2- hydroxymethyl-phenyl}-6-dimethylamino-3,4- dihydro-2H-isoquinolin- 1-one I-71

2-{2-Hydroxymethyl-3- [1-methyl-5-(5- morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6- dihydro-pyridin-3-yl]- phenyl}-6-(1-methyl-cyclopropyl)-3,4- dihydro-2H-isoquinolin- 1-one I-72

2-{3-[5-(4,4-Difluoro- 3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-6′-ylamino)-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl]-2-hydroxymethyl-phenyl}- 6-dimethylamino-3,4- dihydro-2H-isoquinolin-1-one I-73

6-Dimethylamino-2-{2- hydroxymethyl-3-[5-(1- methanesulfonylmethyl-1H-pyrazol-3-ylamino)- 1-methyl-6-oxo-1,6- dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro- 2H-isoquinolin-1-one I-74

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-6-oxo-5-(2- propyl-2H-[1,2,3]triazol-4- ylamino)-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one I-75

6-Dimethylamino-2-(2- hydroxymethyl-3-{1- methyl-6-oxo-5-[5-(2-oxo-pyrrolidin-1-yl)- pyridin-2-ylamino]-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-76

6′-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}-3,4,5,6- tetrahydro- [1,3′]bipyridinyl-2-one I-77

6-Dimethylamino-2-(3- {5-[5-(1,1-dioxo-1λ⁶- [1,2]thiazinan-2-yl)-pyridin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-78

6-Dimethylamino-2-(3- {5-[5-(1,1-dioxo-1λ⁶- isothiazolidin-2-yl)-pyridin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-79

2-(6-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}-pyridin-3- yloxy)-acetamide I-80

6-Cyclopropyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(2-oxa-6-aza-spiro[3.3]hept-6-yl)- pyridin-2-ylamino]-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-81

1-(6-{5-[3-(6- Cyclopropyl-1-oxo-3,4- dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl- phenyl]-1-methyl-2- oxo-1,2-dihydro-pyridin-3-ylamino}- pyridine-3-carbonyl)- piperidine-4-carbonitrile I-82

6-Cyclopropyl-2-(3-{5- [5-(3-ethoxy- pyrrolidine-1-carbonyl)-pyridin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-83

6-Dimethylamino-2-(2- hydroxymethyl-3-{5-[5- (3-methanesulfonyl-propoxy)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-84

6-Dimethylamino-2-(3- {5-[5-(2-hydroxy- ethoxy)-pyridin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl}-2-hydroxymethyl-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-85

2-(3-{5-[5-(4-Acetyl- piperazin-1-yl)-pyridin- 2-ylamino]-1-methyl-6-oxo-1,6-dihydro- pyridin-3-yl}-2- hydroxymethyl-phenyl)-6-dimethylamino-3,4- dihydro-2H-isoquinolin- 1-one I-86

1-(6-{5-[3-(6- Cyclopropyl-1-oxo-3,4- dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl- phenyl]-1-methyl-2- oxo-1,2-dihydro-pyridin-3-ylamino}- pyridine-3-carbonyl)- piperidine-3-carbonitrile I-87

2-(2-acetaldehyde oxime- 3-{1-methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-6- dimethylamino-3,4- dihydro-2H-isoquinolin- 1-one I-88

2-[6-(1-Chloro- cyclopropyl)-1-oxo-3,4- dihydro-1H-isoquinolin-2-yl]-6-{1-methyl-5-[5- (morpholine-4- carbonyl)-pyridin-2-ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}- benzaldehyde I-89

6-(1-Chloro- cyclopropyl)-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(morpholine-4- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one I-90

6-Dimethylamino-2-{2- hydroxymethyl-3-[5-(4- hydroxy-4-methyl-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-6′- ylamino)-1-methyl-6-oxo-1,6-dihydro- pyridin-3-yl]-phenyl}- 3,4-dihydro-2H-isoquinolin-1-one I-91

2-[2-(2- Hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-1-oxo-1,2,3,4- tetrahydro-isoquinolin- 6-yl]-2-methyl-propionitrile I-92

6-(1-Chloro- cyclopropyl)-2-{2- hydroxymethyl-3-[1-methyl-5-(5-morpholin- 4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}- 3,4-dihydro-2H- isoquinolin-1-one I-93

6-Dimethylamino-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(2-oxa-6-aza-spiro[3.3]hept-6-yl)- pyridin-2-ylamino]-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one I-94

1-(2-{2- Hydroxymethyl-3-[1- methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-1-oxo-1,2,3,4-tetrahydro- isoquinolin-6-yl)- cyclopropanecarbonitrile I-95

2-(2-{2- Hydroxymethyl-3-[1- methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-1-oxo-1,2,3,4-tetrahydro- isoquinolin-6-yl)-2- methyl-propionitrile I-96

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-6-oxo-5-(5-piperazin-1-yl-pyridin- 2-ylamino)-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one I-97

6-Dimethylamino-2-{2- hydroxymethyl-3-[5-(5- hydroxymethyl-pyridin-2-ylamino)-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one I-98

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-5-(6-morpholin-4-yl-pyrimidin-4- ylamino)-6-oxo-1,6- dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro- 2H-isoquinolin-1-one I-99

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-5-(5-methyl-isoxazol-3-ylamino)-6- oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one  I-100

6-Dimethylamino-2-{2- hydroxymethyl-3-[5- (isoxazol-3-ylamino)-1-methyl-6-oxo-1,6- dihydro-pyridin-3-yl]- phenyl}-3,4-dihydro-2H-isoquinolin-1-one  I-101

6-(1-Chloro- cyclopropyl)-2-[3-(5-{5- [4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridin- 2-ylamino}-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl)-2- hydroxymethyl-phenyl]- 3,4-dihydro-2H-isoquinolin-1-one  I-102

1-[2-(2- Hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-1-oxo-1,2,3,4- tetrahydro-isoquinolin- 6-yl]-cyclopropanecarbonitrile  I-103

2-(6-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}-pyridin-3- yloxy)-N,N-dimethyl- acetamide  I-104

6-(1-Hydroxy-1- methyl-ethyl)-2-{2- hydroxymethyl-3-[1-methyl-5-(5-morpholin- 4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}- 3,4-dihydro-2H- isoquinolin-1-one  I-105

6-Dimethylamino-2-(2- hydroxymethyl-3-{5-[5- (2-hydroxy- propoxymethyl)-pyridin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one  I-106

(2-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}-pyridin-4-yl)- carbamic acid benzyl ester  I-107

2-{3-[5-(4-Amino- pyridin-2-ylamino)-1- methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2- hydroxymethyl-phenyl}- 6-dimethylamino-3,4-dihydro-2H-isoquinolin- 1-one  I-108

N-(2-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}-pyridin-4-yl)- acetamide  I-109

6-Dimethylamino-2-(2- hydroxymethyl-3-{1- methyl-5-[6-(4-methyl-piperazin-1-yl)- pyrimidin-4-ylamino]-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one  I-110

6-[(2-Hydroxy-ethyl)- methyl-amino]-2-{2- hydroxymethyl-3-[1-methyl-5-(5-morpholin- 4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}- 3,4-dihydro-2H- isoquinolin-1-one  I-111

2-(3-{1- Difluoromethyl-5-[5- (morpholine-4- carbonyl)-pyridin-2-ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-2- hydroxymethyl-phenyl)-6-dimethylamino-3,4- dihydro-2H-isoquinolin- 1-one  I-112

6-Dimethylamino-2-(2- hydroxymethyl-3-{5-[5- (2-methoxy-ethoxy)-pyridin-2-ylamino]-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one  I-113

2-(3-{5-[5-(3,3- Difluoro-azetidin-1- ylmethyl)-pyridin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl}-2-hydroxymethyl-phenyl)- 6-dimethylamino-3,4- dihydro-2H-isoquinolin-1-one  I-114

6-Dimethylamino-2-(3- {5-[5-(1,1-dioxo-1λ⁶- thiomorpholin-4-ylmethyl)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-2- hydroxymethyl-phenyl)- 3,4-dihydro-2H-isoquinolin-1-one  I-115

1-(5-{3-[6-(1-Chloro- cyclopropyl)-1-oxo-3,4- dihydro-1H-isoquinolin-2-yl]-2-hydroxymethyl- phenyl}-1-methyl-2- oxo-1,2-dihydro-pyridin-3-yl)-3-ethyl- urea  I-116

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-6-oxo-5-(5-trifluoromethyl- isoxazol-3-ylamino)- 1,6-dihydro-pyridin-3-yl]-phenyl}-3,4- dihydro-2H-isoquinolin- 1-one  I-117

1-{5-[3-(6-tert-Butyl-1- oxo-3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-yl}-3-methyl-urea  I-118

6-Dimethylamino-2-(2- hydroxymethyl-3-{5-[5- (3-hydroxy-3-methyl-azetidin-1-yl)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one  I-119

6-(1-Chloro- cyclopropyl)-2-{2- hydroxymethyl-3-[5-(4- hydroxy-4-methyl-3,4,5,6-tetrahydro-2H- [1,3′]bipyridinyl-6′- ylamino)-1-methyl-6-oxo-1,6-dihydro- pyridin-3-yl]-phenyl}- 3,4-dihydro-2H-isoquinolin-1-one  I-120

2-(3-{5-[5-(4-Acetyl- piperazin-1-yl)-pyridin- 2-ylamino]-1-methyl-6-oxo-1,6-dihydro- pyridin-3-yl}-2- hydroxymethyl-phenyl)- 6-(1-chloro-cyclopropyl)-3,4- dihydro-2H-isoquinolin- 1-one  I-121

6-(1-Chloro- cyclopropyl)-2-{2- hydroxymethyl-3-[1- methyl-6-oxo-5-(5-piperazin-1-yl-pyridin- 2-ylamino)-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one  I-122

.1-{5-[3-(6-tert-Butyl-1- oxo-3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-yl}-3-ethyl-urea  I-123

6-[Bis-(2-hydroxy- ethyl)-amino]-2-{2- hydroxymethyl-3-[1-methyl-5-(5-morpholin- 4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}- 3,4-dihydro-2H- isoquinolin-1-one  I-124

2-(6-Dimethylamino-1- oxo-3,4-dihydro-1H- isoquinolin-2-yl)-6-{1-methyl-5-[5- (morpholine-4- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- benzoic acid  I-125

6-Dimethylamino-2-{5- fluoro-2- hydroxymethyl-3-[1-methyl-5-(5-morpholin- 4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}- 3,4-dihydro-2H- isoquinolin-1-one  I-126

1-(6-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}-pyridin-3-yl)- pyrrolidine-3-carboxylic acid methyl ester I-127

1-(6-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}-pyridin-3-yl)- pyrrolidine-3-carboxylic acid  I-128

6-Dimethylamino-2-(2- hydroxymethyl-3-{5-[6- (2-methoxy-1-methyl-ethylamino)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one  I-129

6-Dimethylamino-2-{2- hydroxymethyl-3-[5- (1H-imidazol-2-ylamino)-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one  I-130

N-{5-[3-(6- Dimethylamino-1-oxo- 3,4- dihydro-1H-isoquinolin-2-yl)-2-hydroxy- methyl-phenyl]-1- methyl-2-oxo-1,2-dihydro-pyridin-3-yl}- N′-carboxylic acid butyl ester-guanidine  I-131

N-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-yl}-guanidine  I-132

2-(2-Aminomethyl-3- {1-methyl-5-[5- (morpholine-4- carbonyl)-pyridin-2-ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}- phenyl)-6- dimethylamino-3,4-dihydro-2H-isoquinolin- 1-one  I-133

6-Dimethylamino-2-(2- dimethylaminomethyl- 3-{1-methyl-5-[5-(morpholine-4- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one  I-134

1-(5-{2- Hydroxymethyl-3-[6-(1- hydroxy-1-methyl- ethyl)-1-oxo-3,4-dihydro-1H-isoquinolin- 2-yl]-phenyl}-1-methyl- 2-oxo-1,2-dihydro-pyridin-3-yl)-3-methyl- urea  I-135

1-(5-{3-[6-(2-Cyano- 1,1-dimethyl-ethyl)-1- oxo-3,4-dihydro-1H-isoquinolin-2-yl]-2- hydroxymethyl-phenyl}- 1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-3- methyl-urea  I-136

2-[2-Hydroxymethyl-3- (5-{5-[4-(2-methoxy- ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl)-phenyl]-6-(1-methyl- cyclopropyl)-3,4- dihydro-2H-isoquinolin- 1-one I-137

6-Dimethylamino-2-(2- hydroxymethyl-3-{5-[6- ((R)-3-hydroxy-pyrrolidin-1-yl)-pyridin- 2-ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 3,4-dihydro-2H- isoquinolin-1-one  I-138

6-Dimethylamino-2-{3- [5-(5-ethyl-isoxazol-3- ylamino)-1-methyl-6-oxo-1,6-dihydro- pyridin-3-yl]-2- hydroxymethyl-phenyl}- 3,4-dihydro-2H-isoquinolin-1-one  I-139

6-Cyclopropyl-2-{2- hydroxymethyl-3-[1- methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one  I-140

6-Azetidin-1-yl-2-(2- hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one  I-141

1-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-4-fluoro-2- hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-3- methyl-urea  I-142

6-tert-Butyl-2-{2- hydroxymethyl-3-[1- methyl-6-oxo-5-(5-piperazin-1-yl-pyridin- 2-ylamino)-1,6-dihydro- pyridin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one  I-143

2-Cyano-N-{5-[3-(6- dimethylamino-1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}- acetamide  I-144

6-[2-(2-Hydroxy- ethoxy)-1,1-dimethyl- ethyl]-2-{2- hydroxymethyl-3-[1-methyl-5-(5-morpholin- 4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}- 3,4-dihydro-2H- isoquinolin-1-one  I-145

6-(1-Chloro- cyclopropyl)-2-(2- hydroxymethyl-3-{1-methyl-5-[5-(4-methyl- piperazin-1-yl)-pyridin- 2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one  I-146

6-(1-Hydroxy-1- methyl-ethyl)-2-(2- hydroxymethyl-3-{1-methyl-5-[5-(4-methyl- piperazin-1-yl)-pyridin- 2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one  I-147

6-(2-Hydroxy-1,1- dimethyl-ethyl)-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(mropholine-4- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-3,4-dihydro-2H- isoquinolin-1-one  I-148

2-[2-(2- Hydroxymethyl-3-{1- methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin- 2-ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-1-oxo-1,2,3,4- tetrahydro-isoquinolin- 6-yl]-2-methyl-propionitrile  I-149

N-{5-[3-(6- Dimethylamino-1-oxo- 3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-yl}-3-oxo-butyramide  I-150

6-Dimethylamino-2-[2- hydroxymethyl-3-(5-{5- [(2-methoxy-ethylamino)-methyl]- pyridin-2-ylamino}-1- methyl-6-oxo-1,6-dihydro-pyridin-3-yl)- phenyl]-3,4-dihydro-2H- isoquinolin-1-one  I-151

6-Dimethylamino-2-{3- [5-(5-ethyl-4-oxo-4,5- dihydro-1H-imidazol-2-ylamino)-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl]-2-hydroxymethyl-phenyl}- 3,4-dihydro-2H- isoquinolin-1-one  I-152

1-{5-[3-(6-tert-Butyl-1- oxo-3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-yl}-3-(3-dimethylamino- propyl)-urea  I-153

6-Dimethylamino-2-{3- [5-(5-ethyl-1H- imidazol-2-ylamino)-1-methyl-6-oxo-1,6- dihydro-pyridin-3-yl]-2- hydroxymethyl-phenyl}-3,4-dihydro-2H- isoquinolin-1-one  I-154

6-Cyclopropyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridazin-3-yl}-phenyl)-3,4-dihydro-2H- isoquinolin-1-one  I-155

6-Cyclopropyl-2-{2- hydroxymethyl-3-[1- methyl-5-(1-methyl-1H-pyrazol-3-ylamino)-6- oxo-1,6-dihydro- pyridazin-3-yl]-phenyl}-3,4-dihydro-2H- isoquinolin-1-one III-4 

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-5-(1-methyl-1H-pyrazol-3-ylamino)-6- oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one III-5 

1-{5-[3-(6- Dimethylamino-1-oxo- 1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-yl}-3-ethyl-urea III-6 

2-(2-Hydroxymethyl-3- {1-methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-6-(1-methyl- cyclopropyl)-2H- isoquinolin-1-one III-7 

2-{2-Hydroxymethyl-3- [1-methyl-5-(5- morpholin-4-ylmethyl-pyridin-2-ylamino)-6- oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-6-(1-methyl-cyclopropyl)- 2H-isoquinolin-1-one III-8 

2-(2-Hydroxymethyl-3- {1-methyl-5-[5-(4- methyl-piperazine-1-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-6-(1-methyl- cyclopropyl)-2H- isoquinolin-1-one III-9 

6-Cyclopropyl-2-{2- hydroxymethyl-3-[1- methyl-5-(5-morpholin-4-ylmethyl-pyridin-2- ylamino)-6-oxo-1,6- dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin- 1-one III-10

6-Cyclopropyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(4-methyl-piperazine-1-carbonyl)- pyridin-2-ylamino]-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 2H-isoquinolin-1-one III-11

6-Cyclopropyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin- 1-one III-12

6-Cyclopropyl-2-{2- hydroxymethyl-3-[1- methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one III-13

6-Cyclopropyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-3-methyl-2H- isoquinolin-1-one III-14

2-{2-Hydroxymethyl-3- [1-methyl-5-(5- morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6- dihydro-pyridin-3-yl]- phenyl}-6-(1-methyl-cyclopropyl)-2H- isoquinolin-1-one III-15

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro- pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one III-16

6-tert-Butyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin- 1-one III-17

6-Cyclopropyl-3- hydroxymethyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5-(morpholine-4- carbonyl)-pyridin-2- ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}- phenyl)-2H-isoquinolin- 1-one III-18

6-Cyclopropyl-3- hydroxymethyl-2-{2- hydroxymethyl-3-[1-methyl-5-(5-morpholin- 4-yl-pyridin-2-ylamino)- 6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}- 2H-isoquinolin-1-one III-19

6-Cyclopropyl-3- dimethylaminomethyl- 2-{2-hydroxymethyl-3-[1-methyl-5-(5- morpholin-4-yl-pyridin- 2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]- phenyl}-2H-isoquinolin- 1-one III-20

3-tert-Butoxymethyl-6- cyclopropyl-2-{3-[5-(6- fluoro-pyridin-2-ylamino)-1-methyl-6- oxo-1,6-dihydro- pyridin-3-yl]-2-hydroxymethyl-phenyl}- 2H-isoquinolin-1-one III-21

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-5-(6-methylamino-pyridin-2- ylamino)-6-oxo-1,6- dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin- 1-one III-22

6-Dimethylamino-2-(2- hydroxymethyl-3-{1- methyl-5-[6-(4-methyl-piperazin-1-yl)-pyridin- 2-ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin- 1-one III-23

2-{3-[5-(6-Amino- pyridin-2-ylamino)-1- methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2- hydroxymethyl-phenyl}- 6-dimethylamino-2H-isoquinolin-1-one III-24

2-(6-{5-[3-(6- Dimethylamino-1-oxo- 1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}-pyridin-3- yloxy)-N-methyl- acetamide III-25

2-{3-[5-(5,6- Dimethoxy-pyridin-2- ylamino)-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl]-2- hydroxymethyl-phenyl}- 6-dimethylamino-2H-isoquinolin-1-one III-26

6-Dimethylamino-2-(2- hydroxymethyl-3-{5-[5- methoxy-6-(2-methoxy-ethoxy)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 2H-isoquinolin-1-one III-27

6-Dimethylamino-2-(2- hydroxymethyl-3-{5-[6- methoxy-5-(2-methoxy-ethoxy)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 2H-isoquinolin-1-one III-28

2-(3-{5-[5,6-Bis-(2- methoxy-ethoxy)- pyridin-2-ylamino]-1-methyl-6-oxo-1,6- dihydro-pyridin-3-yl}-2- hydroxymethyl-phenyl)-6-dimethylamino-2H- isoquinolin-1-one III-29

6-Dimethylamino-2-{2- hydroxymethyl-3-[1- methyl-5-(2-morpholin-4-yl-pyrimidin-4- ylamino)-6-oxo-1,6- dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin- 1-one III-30

6-Dimethylamino-2-(2- hydroxymethyl-3-{1- methyl-5-[2-(4-methyl-piperazin-1-yl)- pyrimidin-4-ylamino]-6- oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- 2H-isoquinolin-1-one III-31

2-[4-(6-{5-[3-(6- Dimethylamino-1-oxo- 1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}-pyridin-3-yl)- piperazin-1-yl]- isobutyramide III-32

2-(3-{5-[6-(4-Acetyl- piperazin-1-yl)-pyridin- 2-ylamino]-1-methyl-6-oxo-1,6-dihydro- pyridin-3-yl}-2- hydroxymethyl-phenyl)-6-dimethylamino-2H- isoquinolin-1-one III-33

6-Dimethylamino-2-{3- [5-(5-ethyl-1H-pyrazol- 3-ylamino)-1-methyl-6-oxo-1,6-dihydro- pyridin-3-yl]-2- hydroxymethyl-phenyl}-2H-isoquinolin-1-one III-34

6-Dimethylamino-2-(3- {5-[5-(2-hydroxy- ethoxy)-6-(2-methoxy-ethoxy)-pyridin-2- ylamino]-1-methyl-6- oxo-1,6-dihydro-pyridin-3-yl}-2- hydroxymethyl-phenyl)- 2H-isoquinolin-1-one III-35

6-Cyclopropyl-2-(2- hydroxymethyl-3-{1- methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridazin-3-yl}-phenyl)-2H-isoquinolin- 1-one III-36

2-(2-Hydroxymethyl-3- {1-methyl-5-[5- (morpholine-4-carbonyl)-pyridin-2- ylamino]-6-oxo-1,6- dihydro-pyridazin-3-yl}-phenyl)-6-(1-methyl- cyclopropyl)-2H- isoquinolin-1-one

Pharmacological Activity

The pyridinone and pyridazinone derivatives described herein are kinaseinhibitors, in particular Btk inhibitors. These inhibitors can be usefulfor treating one or more diseases responsive to kinase inhibition,including diseases responsive to Btk inhibition and/or inhibition ofB-cell proliferation, in mammals. Without wishing to be bound to anyparticular theory, it is believed that the interaction of the compoundsof the invention with Btk results in the inhibition of Btk activity andthus in the pharmaceutical utility of these compounds. Accordingly, theinvention includes a method of treating a mammal, for instance a human,having a disease responsive to inhibition of Btk activity, and/orinhibiting B-cell proliferation, comprising administrating to the mammalhaving such a disease, an effective amount of at least one chemicalentity provided herein. An effective concentration may be ascertainedexperimentally, for example by assaying blood concentration of thecompound, or theoretically, by calculating bioavailability. Otherkinases that may be affected in addition to Btk include, but are notlimited to, other tyrosine kinases and serine/threonine kinases.

Kinases play notable roles in signaling pathways controlling fundamentalcellular processes such as proliferation, differentiation, and death(apoptosis). Abnormal kinase activity has been implicated in a widerange of diseases, including multiple cancers, autoimmune and/orinflammatory diseases, and acute inflammatory reactions. Themultifaceted role of kinases in key cell signaling pathways provides asignificant opportunity to identify novel drugs targeting kinases andsignaling pathways.

An embodiment includes a method of treating a patient having anautoimmune and/or inflammatory disease, or an acute inflammatoryreaction responsive to inhibition of Btk activity and/or B-cellproliferation.

Autoimmune and/or inflammatory diseases that can be affected usingcompounds and compositions according to the invention include, but arenot limited to: psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, Sjogren's disease, tissue graft rejection, and hyperacuterejection of transplanted organs, asthma, systemic lupus erythematosus(and associated glomerulonephritis), dermatomyositis, multiplesclerosis, scleroderma, vasculitis (ANCA-associated and othervasculitides), autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome (and associated glomerulonephritis and pulmonaryhemorrhage), atherosclerosis, rheumatoid arthritis, chronic Idiopathicthrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease,Alzheimer's disease, diabetes, septic shock, and myasthenia gravis.

Included herein are methods of treatment in which at least one chemicalentity provided herein is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor receptor (TNF) receptors antagonists, immunosuppressantsand methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include by are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may he cortisone, dexamethasone, methylprednisolone,prednisolone, prednisolone sodium phosphate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compoundsuch as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-C5 monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asan immunosuppressant compound chosen from methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

B-cells and B-cell precursors expressing BTK have been implicated in thepathology of B-cell malignancies, including, but not limited to, B-celllymphoma, lymphoma (including Hodgkin's and non-Hodgkin's lymphoma),hairy cell lymphoma, multiple myeloma, chronic and acute myelogenousleukemia and chronic and acute lymphocytic leukemia.

BTK has been shown to be an inhibitor of the Fas/APO-1 (CD-95) deathinducing signaling complex (DISC) in B-lineage lymphoid cells. The fateof leukemia/lymphoma cells may reside in the balance between theopposing proapoptotic effects of caspases activated by DISC and anupstream anti-apoptotic regulatory mechanism involving BTK and/or itssubstrates (Vassilev et al, J. Biol. Chem. 1998, 274, 1646-1656).

It has also been discovered that BTK inhibitors are useful aschemosensitizing agents, and, thus, are useful in combination with otherchemotherapeutic drugs, in particular, drugs that induce apoptosis.Examples of other chemotherapeutic drugs that can be used in combinationwith chemosensitizing BTK inhibitors include topoisomerase I inhibitors(camptothecin or topotecan), topoisomerase II inhibitors (e.g.daunomycin and etoposide), alkylating agents (e.g. cyclophosphamide,melphalan and BCNU), tubulin directed agents (e.g. taxol andvinblastine), and biological agents (e.g. antibodies such as anti CD20antibody, IDEC 8, immunotoxins, and cytokines).

Btk activity has also be associated with some leukemias expressing thebcr-abl fusion gene resulting from translocation of parts of chromosome9 and 22. This abnormality is commonly observed in chronic myelogenousleukemia. Btk is constitutively phosphorylated by the bcr-abl kinasewhich initiates downstream survival signals which circumvents apoptosisin bcr-abl cells. (N. Feldhahn et al. J. Exp. Med. 2005201(11):1837-1852)

Dosage and Administration

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms and carriers. Oraladministration can be in the form of tablets, coated tablets, dragees,hard and soft gelatine capsules, solutions, emulsions, syrups, orsuspensions. Compounds of the present invention are efficacious whenadministered by other routes of administration including continuous(intravenous drip) topical parenteral, intramuscular, intravenous,subcutaneous, transdermal (which may include a penetration enhancementagent), buccal, nasal, inhalation and suppository administration, amongother routes of administration. The preferred manner of administrationis generally oral using a convenient daily dosing regimen which can beadjusted according to the degree of affliction and the patient'sresponse to the active ingredient.

A compound or compounds of the present invention, as well as theirpharmaceutically useable salts, together with one or more conventionalexcipients, carriers, or diluents, may be placed into the form ofpharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. A typical preparation will contain from about 5% toabout 95% active compound or compounds (w/w). The term “preparation” or“dosage form” is intended to include both solid and liquid formulationsof the active compound and one skilled in the art will appreciate thatan active ingredient can exist in different preparations depending onthe target organ or tissue and on the desired dose and pharmacokineticparameters.

The term “excipient” as used herein refers to a compound that is usefulin preparing a pharmaceutical composition, generally safe, non-toxic andneither biologically nor otherwise undesirable, and includes excipientsthat are acceptable for veterinary use as well as human pharmaceuticaluse. The compounds of this invention can be administered alone but willgenerally be administered in admixture with one or more suitablepharmaceutical excipients, diluents or carriers selected with regard tothe intended route of administration and standard pharmaceuticalpractice.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

A “pharmaceutically acceptable salt” form of an active ingredient mayalso initially confer a desirable pharmacokinetic property on the activeingredient which were absent in the non-salt form, and may evenpositively affect the pharmacodynamics of the active ingredient withrespect to its therapeutic activity in the body. The phrase“pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier may beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material. In powders,the carrier generally is a finely divided solid which is a mixture withthe finely divided active component. In tablets, the active componentgenerally is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers include but are not limited to magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Solid form preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Liquid formulations also are suitable for oral administration includeliquid formulation including emulsions, syrups, elixirs, aqueoussolutions, aqueous suspensions. These include solid form preparationswhich are intended to be converted to liquid form preparations shortlybefore use. Emulsions may be prepared in solutions, for example, inaqueous propylene glycol solutions or may contain emulsifying agentssuch as lecithin, sorbitan monooleate, or acacia. Aqueous solutions canbe prepared by dissolving the active component in water and addingsuitable colorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into to the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polyactic acid.

Suitable formulations along with pharmaceutical carriers, diluents andexpcipients are described in Remington: The Science and Practice ofPharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19thedition, Easton, Pa. A skilled formulation scientist may modify theformulations within the teachings of the specification to providenumerous formulations for a particular route of administration withoutrendering the compositions of the present invention unstable orcompromising their therapeutic activity.

The modification of the present compounds to render them more soluble inwater or other vehicle, for example, may be easily accomplished by minormodifications (salt formulation, esterification, etc.), which are wellwithin the ordinary skill in the art. It is also well within theordinary skill of the art to modify the route of administration anddosage regimen of a particular compound in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectin patients.

The term “therapeutically effective amount” as used herein means anamount required to reduce symptoms of the disease in an individual. Thedose will be adjusted to the individual requirements in each particularcase. That dosage can vary within wide limits depending upon numerousfactors such as the severity of the disease to be treated, the age andgeneral health condition of the patient, other medicaments with whichthe patient is being treated, the route and form of administration andthe preferences and experience of the medical practitioner involved. Fororal administration, a daily dosage of between about 0.01 and about 1000mg/kg body weight per day should be appropriate in monotherapy and/or incombination therapy. A preferred daily dosage is between about 0.1 andabout 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg bodyweight and most preferred 1.0 and about 10 mg/kg body weight per day.Thus, for administration to a 70 kg person, the dosage range would beabout 7 mg to 0.7 g per day. The daily dosage can be administered as asingle dosage or in divided dosages, typically between 1 and 5 dosagesper day. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect for theindividual patient is reached. One of ordinary skill in treatingdiseases described herein will be able, without undue experimentationand in reliance on personal knowledge, experience and the disclosures ofthis application, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease and patient.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Examples Example 1

2-(3-Bromo-phenyl)-3-(3-t-butyl-phenylamino)-acrylic acid ethyl ester

(3-Bromo-phenyl)-acetic acid benzyl ester (1 g, 4.12 mmol) was dissolvedin ethyl formate (8 mL, 99 mmol). Sodium hydride (60%, 660 mg, 16.5mmol) was added. After stirring overnight, this was quenched with 2 Maq. HCl. This was partitioned between ethyl acetate and water. The ethylacetate layer was washed with water, washed with brine, dried overanhydrous magnesium sulfate, and concentrated in vacuo.

This material (0.65 g) and 3-t-butyl-aniline (0.37 mL, 2.48 mmol) werestirred in 1 mL ethanol for 18 hours. This was concentrated in vacuo andpurified by flash chromatography (gradient elution 5 to 20% ethylacetate/hexanes) to yield 2-(3-Bromo-phenyl)-3-(3-t-butyl-phenylamino)-acrylic acid ethyl ester (0.5 mg). MS (ESI)402 (M+H)⁺.

Example 2

3-(3-Bromo-phenyl)-7-tort-butyl-1H-quinolin-4-one

To 2-(3-Bromo-phenyl)-3-(3-tert-butyl-phenylamino)-acrylic acid ethylester (151 mg, 0.388 mmol) was added 10 g of polyphosphoric acid. Theresulting mixture was heated at 140° C. for 90 minutes. 80 mL of waterwas added. The mixture was stirred for 40 minutes. The resultingprecipitate was filtered, washed with water, and air dried for 3 days toyield 3-(3-Bromo-phenyl)-7-tert-butyl-1H-quinolin-4-one (123 mg. 0.345mmol). MS (ESI) 356 (M+H)⁺.

Example 3

7-tert-Butyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-quinolin-4-one

3-(3-Bromo-phenyl)-7-tert-butyl-1H-quinolin-4-one (119 mg, 0.334 mmol),bis(pinacolato)diboron (102 mg, 0.401 mmol), and potassium acetate (98mg, 1.0 mmol) were deposited in a sealed vessel with 2 mL of DMSO. Argonwas bubbled through the mixture for 1 minute.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (8.0 mg, 0.0098 mmol) was added. Argon was bubbledthrough the mixture for one minute and the lid was tightly sealed. Theresulting mixture was heated at 80° C. for 18 hours prior to beingpartitioned between ethylacetate and water. The ethylacetate layer waswashed with brine, dried over anhydrous magnesium sulfate, concentratedin vacuo, and purified by flash chromatography (gradient elution 25 to50% ethylacetate/hexanes) to yield7-tert-Butyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-quinolin-4-one (77 mg, 0.19 mmol).MS (ESI) 404.1 (M+H)⁺.

Example 4

7-tert-Butyl-3-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1H-quinolin-4-one

A solution of 5-Bromo-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (19 mg, 0.050 mmol),7-tert-Butyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-quinolin-4-one (20 mg, 0.05 mmol),tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0.0052 mmol), andsodium carbonate (16 mg, 0.15 mmol) in 2 mL 1,2-dimethoxyethane and 1 mLwater was microwaved at 170° C. for 12.5 minutes. The resulting mixturewas partitioned between ethyl acetate and water. The ethyl acetate layerwas washed with brine, dried over anhydrous magnesium sulfate,concentrated in vacuo, and purified by preparative TLC (5%methanol/dichloromethane) to yield7-tert-Butyl-3-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1H-quinolin-4-one(5.7 mg, 0.0085 mmol). MS (ESI) 590.1 (M+H)⁺.

Example 5

2-(3-Bromo-2-methyl-phenyl)-3-(3-dimethylamino-phenylamino) -acrylicacid ethyl ester

(3-Bromo-2-methyl-phenyl)-acetic acid benzyl ester (421 mg, 1.32 mmol)was dissolved in ethyl formate (2.5 mL, 31 mmol). Sodium hydride (95%,67 mg, 2.6 mmol) was added. After stirring for 30 minutes, this wasquenched with 1M aq. HCl. This was partitioned between ethyl acetate andwater. The ethyl acetate layer was washed with water, washed with brine,dried over anhydrous magnesium sulfate, and concentrated in vacuo.

A portion of this material and N,N-Dimethyl-benzene-1,3-diamine (96 mg,0.70 mmol) were stirred in 1 mL ethanol for 18 hours. This wasconcentrated in vacuo and purified by flash chromatography (gradientelution 5 to 20% ethyl acetate/hexanes) to yield2-(3-Bromo-2-methyl-phenyl)-3-(3-dimethylamino-phenylamino) -acrylicacid ethyl ester (164 mg, 0.407 mmol). MS (ESI) 405.0 (M+H)⁺.

Example 6

3-(3-Bromo-2-methyl-phenyl)-7-dimethylamino-1H-quinolin-4-one

To 2-(3-Bromo-2-methyl-phenyl)-3-(3-dimethylamino-phenylamino) -acrylicacid ethyl ester (100 mg, 0.248 mmol) was added 4 g polyphosphoric acid.This stirred at 140° C. for 10 minutes. 50 ml water was added and themixture was stirred. The resulting precipitate was filtered and washedwith water. The filtrate was extracted with 10% methanol/dichloromethanesolution. The organic layer was dried over anhydrous magnesium sulfateand concentrated in vacuo. The resulting residue was combined with theprecipitate and purified by flash chromatography (gradient elution 2 to5% methanol/dichloromethane) to yield3-(3-Bromo-2-methyl-phenyl)-7-dimethylamino-1H -quinolin-4-one (22 mg,0.062 mmol). MS (ESI) 357.0 (M+H)⁺.

Example 7

1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one

5-Bromo-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (1.00 g, 2.55 mmol), bis(pinacolato)diboron (1.94 g, 7.64mmol), potassium acetate(750 mg, 7.64 mmol),2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl(121 mg,0.254 mmol), and bis(dibenzylidineacetone)palladium(0) (73 mg, 0.13mmol) were dissolved in 15 ml degassed 1,4-dioxane. The headspace of thevessel was evacuated and backfilled with argon 5 times. This was heatedat 110° C. for 3 hours. This was partitioned between ethyl acetate andwater. The ethyl acetate layer was washed with brine, dried overanhydrous magnesium sulfate, concentrated in vacuo, and purified byflash chromatography (gradient elution 2 to 8% methanol/dichloromethane)to yield1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (0.798 g, 1.81 mmol). MS(ESI) 441.2 (M+H)⁺.

Example 8

7-Dimethylamino-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1H-quinolin-4-one

ToMethyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one(27 mg, 0.062 mmol),3-(3-Bromo-2-methyl-phenyl)-7-dimethylamino-1H-quinolin-4-one (22 mg,0.062 mmol), potassium phosphate (26 mg, 0.12 mmol),2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i -propyl-1,1′-biphenyl (1.7 mg,0.0036 mmol), and bis(dibenzylidineacetone)palladium(0) (1.0 mg, 0.0018mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace ofthe vessel was evacuated and backfilled with argon 4 times. This washeated at 100° C. for 1 hour. This was partitioned between ethyl acetateand water. The ethyl acetate layer was washed with brine, dried overanhydrous magnesium sulfate, concentrated in vacuo, and purified bypreparative TLC (5% methanol/dichloromethane) to yield7-Dimethylamino-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1H-quinolin-4-one(14 mg, 0.024 mmol). MS (ESI) 591.1 (M+H)⁺.

1. A compound of Formula III,

wherein: R is H, —R¹, —R¹—R²—R³, —R¹—R³, or —R²—R³; R¹ is aryl,heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionallysubstituted with one or more lower alkyl, hydroxy, hydroxy lower alkyl,lower alkoxy, halo, nitro, amino, amido, cyano, oxo, or halo-loweralkyl; R² is —C(═O), —O, —C(═O)O, —C(═O)NR^(2′), or —S(═O)₂; R^(2′) is Hor lower alkyl; R³ is H or R⁴; R⁴ is lower alkyl, amino, aryl,arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl,cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkylheterocycloalkyl, or heterocycloalkyl alkyl, and is optionallysubstituted with one or more lower alkyl, hydroxy, hydroxy lower alkyl,lower alkoxy, halo, nitro, amino, amido, acyl, cyano, or halo-loweralkyl; X is CH or N; Y¹ is H, lower alkyl, or lower haloalkyl; each Y²is independently halogen or lower alkyl, wherein lower alkyl isoptionally substituted with one or more substituents selected from thegroup consisting of hydroxy, lower alkoxy, lower haloalkoxy, lowerhaloalkyl, carboxy, amino, and halogen; n is 0, 1, 2, or 3; Y³ is H,halogen, or lower alkyl, wherein lower alkyl is optionally substitutedwith one or more substituents selected from the group consisting ofhydroxy, lower alkoxy, amino, and halogen; m is 0 or 1; Y⁴ is Y^(4a),Y^(4b), Y^(4c), or Y^(4d); Y^(4a) is H or halogen; Y^(4b) is loweralkyl, optionally substituted with one or more substituents selectedfrom the group consisting of haloalkyl, halogen, hydroxy, amino, cyano,and lower alkoxy; Y^(4c) is lower cycloalkyl, optionally substitutedwith one or more substituents selected from the group consisting oflower alkyl, lower haloalkyl, halogen, hydroxy, hydroxyl lower alkyl,amino, cyano, and lower alkoxy; and Y^(4d) is amino, optionallysusbstituted with one or more lower alkyl, alkoxy lower alkyl, orhydroxy lower alkyl; or a pharmaceutically acceptable salt thereof. 2.The compound of claim 1, wherein Y¹ is methyl.
 3. The compound of claim2, wherein X is CH.
 4. The compound of claim 3, wherein n is 1 and m is0.
 5. The compound of claim 4, wherein Y³ is H.
 6. The compound of claim5, wherein Y² is methyl.
 7. The compound of claim 5, wherein Y² ishydroxymethyl.
 8. The compound of claim 5, wherein Y² is hydroxyethyl.9. The compound of claim 5, wherein Y² is halogen.
 10. The compound ofclaim 7, wherein Y⁴ is

wherein, Y⁵ is halogen, lower alkyl, or lower haloalkyl.
 11. Thecompound of claim 7, wherein Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.12. The compound of claim 7, wherein Y⁴ is

wherein, Y⁵ and Y⁶ are independently H or lower alkyl.
 13. The compoundof claim 7, wherein Y⁴ is

wherein, Y⁵ and Y⁶ are independently H, lower alkyl, or lower haloalkyl.14. The compound of claim 10, wherein R is —R¹—R²—R³; R¹ is phenyl orpyridyl; R² is —C(═O); R³ is R⁴; and R⁴ is morpholine or piperazine,optionally substituted with one or more lower alkyl.
 15. The compound ofclaim 11, wherein R is —R¹—R²—R³; R¹ is phenyl or pyridyl; R² is —C(═O);R³ is R⁴; and R⁴ is morpholine or piperazine, optionally substitutedwith one or more lower alkyl.
 16. The compound of claim 12, wherein R is—R¹—R²—R³; R¹ is phenyl or pyridyl; R² is —C(═O); R³ is R⁴; and R⁴ ismorpholine or piperazine, optionally substituted with one or more loweralkyl.
 17. The compound of claim 13, wherein R is —R¹—R²—R³; R¹ isphenyl or pyridyl; R² is —C(═O); R³ is R⁴; and R⁴ is morpholine orpiperazine, optionally substituted with one or more lower alkyl.
 18. Thecompound of claim 1, wherein Formula III is selected from the groupconsisting of:6-Dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;6-Dimethylamino-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;1-{5-[3-(6-Dimethylamino-1-oxo-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-3-ethyl-urea;2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-(1-methyl-cyclopropyl)-2H-isoquinolin-1-one;2-{2-Hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-ylmethyl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-6-(1-methyl-cyclopropyl)-2H-isoquinolin-1-one;2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-(1-methyl-cyclopropyl)-2H-isoquinolin-1-one;6-Cyclopropyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-ylmethyl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;6-Cyclopropyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one; -6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3-methyl-2H-isoquinolin-1-one;2-{2-Hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-6-(1-methyl-cyclopropyl)-2H-isoquinolin-1-one;6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;6-tert-Butyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;6-Cyclopropyl-3-hydroxymethyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;6-Cyclopropyl-3-hydroxymethyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;6-Cyclopropyl-3-dimethylaminomethyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;3-tert-Butoxymethyl-6-cyclopropyl-2-{3-[5-(6-fluoro-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-2H-isoquinolin-1-one;6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(6-methylamino-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;2-{3-[5-(6-Amino-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-6-dimethylamino-2H-isoquinolin-1-one;2-(6-{5-[3-(6-Dimethylamino-1-oxo-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yloxy)-N-methyl-acetamide;2-{3-[5-(5,6-Dimethoxy-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-6-dimethylamino-2H-isoquinolin-1-one;6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[5-methoxy-6-(2-methoxy-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;6-Dimethylamino-2-(2-hydroxymethyl-3-{5-[6-methoxy-5-(2-methoxy-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;2-(3-{5-[5,6-Bis-(2-methoxy-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-2H-isoquinolin-1-one;6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(2-morpholin-4-yl-pyrimidin-4-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one;6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one;2-[4-(6-{5-[3-(6-Dimethylamino-1-oxo-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-piperazin-1-yl]-isobutyramide;2-(3-{5-[6-(4-Acetyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-dimethylamino-2H-isoquinolin-1-one;6-Dimethylamino-2-{3-[5-(5-ethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-hydroxymethyl-phenyl}-2H-isoquinolin-1-one;6-Dimethylamino-2-(3-{5-[5-(2-hydroxy-ethoxy)-6-(2-methoxy-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-2H-isoquinolin-1-one;6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-isoquinolin-1-one;and2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-6-(1-methyl-cyclopropyl)-2H-isoquinolin-1-one.
 19. A method for treating an arthritis comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the compound of claim
 1. 20. A method for treating arthritiscomprising co-administering to a patient in need thereof atherapeutically effective amount of an anti-inflammatory compound incombination with the compound of claim
 1. 21. A pharmaceuticalcomposition comprising the Btk inhibitor compound of claim 1 admixedwith at least one pharmaceutically acceptable carrier, excipient ordiluent.